2022

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17 pages, 947 KiB

Open AccessReview

Polyphenols as Lung Cancer Chemopreventive Agents by Targeting microRNAs

by Jing Li, Xianmei Zhong, Yueshui Zhao, Jing Shen, Chalermchai Pilapong and Zhangang Xiao

Molecules 2022, 27(18), 5903; https://doi.org/10.3390/molecules27185903 - 11 Sep 2022

Cited by 6 | Viewed by 2445

Lung cancer is the second leading cause of cancer-related death worldwide. In recent decades, investigators have found that microRNAs, a group of non-coding RNAs, are abnormally expressed in lung cancer, and play important roles in the initiation and progression of lung cancer. These [...] Read more.

Lung cancer is the second leading cause of cancer-related death worldwide. In recent decades, investigators have found that microRNAs, a group of non-coding RNAs, are abnormally expressed in lung cancer, and play important roles in the initiation and progression of lung cancer. These microRNAs have been used as biomarkers and potential therapeutic targets of lung cancer. Polyphenols are natural and bioactive chemicals that are synthesized by plants, and have promising anticancer effects against several kinds of cancer, including lung cancer. Recent studies identified that polyphenols exert their anticancer effects by regulating the expression levels of microRNAs in lung cancer. Targeting microRNAs using polyphenols may provide a novel strategy for the prevention and treatment of lung cancer. In this review, we reviewed the effects of polyphenols on oncogenic and tumor-suppressive microRNAs in lung cancer. We also reviewed and discussed the potential clinical application of polyphenol-regulated microRNAs in lung cancer treatment. Full article

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17 pages, 7135 KiB

Open AccessArticle

The Inhibition of Gastric Cancer Cells’ Progression by 23,24-Dihydrocucurbitacin E through Disruption of the Ras/Raf/ERK/MMP9 Signaling Pathway

by Huiping Liu, Huijuan Wang, Aijun Dong, Xiaoshuang Huo, Huaxiang Wang, Junchi Wang and Jianyong Si

Molecules 2022, 27(9), 2697; https://doi.org/10.3390/molecules27092697 - 22 Apr 2022

Cited by 8 | Viewed by 1835

Abstract

Gastric cancer is considered to be one of the most common causes of cancer death worldwide due to its high recurrence and metastasis rates. The molecule 23,24-Dihydrocucurbitacin E (DHCE) is a cucurbitacin-derived tetracyclic triterpenoid compound that has anti-tumor activity, but the exact mechanism [...] Read more.

Gastric cancer is considered to be one of the most common causes of cancer death worldwide due to its high recurrence and metastasis rates. The molecule 23,24-Dihydrocucurbitacin E (DHCE) is a cucurbitacin-derived tetracyclic triterpenoid compound that has anti-tumor activity, but the exact mechanism remains to be elucidated. This research aimed to explore the effects of DHCE on human gastric cancer cells and the possible mechanisms. The results showed that DHCE suppressed proliferation, migration, and invasion of gastric cancer cells, as well as induced apoptosis and G2/M phase arrest. Mechanistically, the potential targets and pathways of DHCE were predicted using database screening and verified using a molecular docking study, fluorescence staining, and Western blot. The results indicated that DHCE obviously inhibited the kinase activity of ERK2 via targeting its ATP-binding domain, destroyed F-actin microfilament, and reduced the expression levels of Ras, p-c-Raf, ERK, p-ERK, and MMP9 proteins. Collectively, our study demonstrated that DHCE suppressed gastric cancer cells’ proliferation, migration, and invasion through targeting ERK2 and disrupting the Ras/Raf/ERK/MMP9 signaling pathway. These properties make DHCE a promising candidate drug for the further design and development of novel and effective Ras/Raf/ERK/MMP9 pathway inhibitors for treating gastric cancer. Full article

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2021

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35 pages, 5941 KiB

Open AccessArticle

Novel Strategies for Solubility and Bioavailability Enhancement of Bufadienolides

by Huili Shao, Bingqian Li, Huan Li, Lei Gao, Chao Zhang, Huagang Sheng and Liqiao Zhu

Molecules 2022, 27(1), 51; https://doi.org/10.3390/molecules27010051 - 22 Dec 2021

Cited by 13 | Viewed by 3401

Abstract

Toad venom contains a large number of bufadienolides, which have a variety of pharmacological activities, including antitumor, cardiovascular, anti-inflammatory, analgesic and immunomodulatory effects. The strong antitumor effect of bufadienolides has attracted considerable attention in recent years, but the clinical application of bufadienolides is [...] Read more.

Toad venom contains a large number of bufadienolides, which have a variety of pharmacological activities, including antitumor, cardiovascular, anti-inflammatory, analgesic and immunomodulatory effects. The strong antitumor effect of bufadienolides has attracted considerable attention in recent years, but the clinical application of bufadienolides is limited due to their low solubility and poor bioavailability. In order to overcome these shortcomings, many strategies have been explored, such as structural modification, solid dispersion, cyclodextrin inclusion, microemulsion and nanodrug delivery systems, etc. In this review, we have tried to summarize the pharmacological activities and structure–activity relationship of bufadienolides. Furthermore, the strategies for solubility and bioavailability enhancement of bufadienolides also are discussed. This review can provide a basis for further study on bufadienolides. Full article

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13 pages, 4621 KiB

Open AccessArticle

Harmine Hydrochloride Mediates the Induction of G2/M Cell Cycle Arrest in Breast Cancer Cells by Regulating the MAPKs and AKT/FOXO3a Signaling Pathways

by Chae Won Ock and Gi Dae Kim

Molecules 2021, 26(21), 6714; https://doi.org/10.3390/molecules26216714 - 05 Nov 2021

Cited by 14 | Viewed by 2221

Abstract

Breast cancer (BC) is one of the most common causes of death among women worldwide. Recently, interest in novel approaches for BC has increased by developing new drugs derived from natural products with reduced side effects. This study aimed to treat BC cells [...] Read more.

Breast cancer (BC) is one of the most common causes of death among women worldwide. Recently, interest in novel approaches for BC has increased by developing new drugs derived from natural products with reduced side effects. This study aimed to treat BC cells with harmine hydrochloride (HMH) to identify its anticancer effects and mechanisms. HMH treatment suppressed cell growth, migration, invasion, and colony formation in MCF-7 and MDA-MB-231 cells, regardless of the hormone signaling. It also reduced the phosphorylation of PI3K, AKT, and mTOR and increased FOXO3a expression. Additionally, HMH treatment increased p38 phosphorylation in MCF-7 cells and activated c-Jun N-terminal kinase (JNK) phosphorylation in MDA-MB-231 cells in a dose-dependent manner, where activated p38 and JNK increased FOXO3a expression. Activated FOXO3a increased the expression of p53, p21, and their downstream proteins, including p-cdc25, p-cdc2, and cyclin B1, to induce G2/M cell cycle arrest. Furthermore, HMH inhibited the PI3K/AKT/mTOR pathway by significantly reducing p-AKT expression in combination with LY294002, an AKT inhibitor. These results indicate that mitogen-activated protein kinases (MAPKs) and AKT/FOXO3a signaling pathways mediate the induction of cell cycle arrest following HMH treatment. Therefore, HMH could be a potential active compound for anticancer bioactivity in BC cells. Full article

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16 pages, 3894 KiB

Open AccessArticle

(−)-6-epi-Artemisinin, a Natural Stereoisomer of (+)-Artemisinin in the Opposite Enantiomeric Series, from the Endemic Madagascar Plant Saldinia proboscidea, an Atypical Source

by Saholinirina Randrianarivo, Claudine Rasolohery, Sitraka Rafanomezantsoa, Heriniaina Randriamampionona, Liti Haramaty, Roger Marie Rafanomezantsoa and Eric H. Andrianasolo

Molecules 2021, 26(18), 5540; https://doi.org/10.3390/molecules26185540 - 12 Sep 2021

Cited by 2 | Viewed by 2717

Abstract

Chemical and biological investigation of the Madagascar endemic plant Saldinia proboscidea led to the isolation of an isomer of artemisinin, (−)-6-epi-artemisinin (2). Its structure was elucidated using a combination of NMR and mass spectrometry. The absolute configuration was established by chemical [...] Read more.

Chemical and biological investigation of the Madagascar endemic plant Saldinia proboscidea led to the isolation of an isomer of artemisinin, (−)-6-epi-artemisinin (2). Its structure was elucidated using a combination of NMR and mass spectrometry. The absolute configuration was established by chemical syntheses of compound 2 as well as a new stereoisomer (3). The comparable bioactivities of artemisinin (1) and its isomer (−)-6-epi-artemisinin (2) revealed that this change in configuration was not critical to their biological properties. Bioactivity was assessed using an apoptosis induction assay, a SARS-CoV-2 inhibitor assay, and a haematin polymerization inhibitory activity (HPIA) assay. This is the first report of an artemisinin-related compound from a genus not belonging to Artemisia and it is the first isolation of an artemisinin-related natural product that is the opposite enantiomeric series relative to artemisinin from Artemisia annua. Full article

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15 pages, 3210 KiB

Open AccessArticle

Davidone C Induces the Death of Hepatocellular Carcinoma Cells by Promoting Apoptosis and Autophagy

by Ping Song, Huiqi Huang, Yuanren Ma, Chaoqun Wu, Xinzhou Yang and Ho-Young Choi

Molecules 2021, 26(17), 5219; https://doi.org/10.3390/molecules26175219 - 28 Aug 2021

Cited by 3 | Viewed by 1761

Abstract

Davidone C is a newly discovered flavonoid compound purified from the ethyl acetate-soluble fraction of Sophora davidii (Franch.) Skeels. This study explored the anti-tumor activity of davidone C on hepatocellular carcinoma HepG2 and Bel-7402 cells and its mechanism through MTT method, morphological observation, [...] Read more.

Davidone C is a newly discovered flavonoid compound purified from the ethyl acetate-soluble fraction of Sophora davidii (Franch.) Skeels. This study explored the anti-tumor activity of davidone C on hepatocellular carcinoma HepG2 and Bel-7402 cells and its mechanism through MTT method, morphological observation, flow cytometry and Western blotting. The results showed that davidone C significantly inhibited the proliferation of HepG2 and Bel-7402 cells in a time- and dose-dependent manner. The morphological changes of apoptotic cells can be observed under an inverted microscope, such as cell floating, chromosome condensation, apoptotic bodies, and other phenomena. The expressions of Bax, cleaved caspase-9, cleaved caspase-3 and cleaved PARP increased with the increase of dosage while Bcl-2 decreased, suggesting that the apoptotic mechanism might be related to the mitochondrial apoptotic pathway. Moreover, davidone C administration can down-regulate the expression of Grp78, and simultaneously up-regulate the expression of caspase-7 and caspase-12, indicating that the apoptotic mechanism might be related to the ERS pathway. In addition, davidone C can down-regulate the expression of p62, and simultaneously up-regulate the expression of LC3-I and LC3-II with a quantitative dependence, suggesting that the mechanism of apoptosis may be related to the autophagy signal pathway. All these results showed davidone C has potential effects on hepatocellular carcinoma. Full article

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15 pages, 3987 KiB

Open AccessArticle

Cytotoxicity of a Lipid-Rich Extract from Native Mexican Avocado Seed (Persea americana var. drymifolia) on Canine Osteosarcoma D-17 Cells and Synergistic Activity with Cytostatic Drugs

by Salvador Padilla-Arellanes, Rafael Salgado-Garciglia, Marisol Báez-Magaña, Alejandra Ochoa-Zarzosa and Joel Edmundo López-Meza

Molecules 2021, 26(14), 4178; https://doi.org/10.3390/molecules26144178 - 09 Jul 2021

Cited by 3 | Viewed by 2449

Abstract

Osteosarcoma is the most common malignant bone tumor in both children and dogs. It is an aggressive and metastatic cancer with a poor prognosis for long-term survival. The search for new anti-cancer drugs with fewer side effects has become an essential goal for [...] Read more.

Osteosarcoma is the most common malignant bone tumor in both children and dogs. It is an aggressive and metastatic cancer with a poor prognosis for long-term survival. The search for new anti-cancer drugs with fewer side effects has become an essential goal for cancer chemotherapy; in this sense, the bioactive compounds from avocado have proved their efficacy as cytotoxic molecules. The objective of this study was to determine the cytotoxic and antiproliferative effect of a lipid-rich extract (LEAS) from Mexican native avocado seed (Persea americana var. drymifolia) on canine osteosarcoma D-17 cell line. Also, the combined activity with cytostatic drugs was evaluated. LEAS was cytotoxic to D-17 cells in a concentration-dependent manner with an IC₅₀ = 15.5 µg/mL. Besides, LEAS induced caspase-dependent cell apoptosis by the extrinsic and intrinsic pathways. Moreover, LEAS induced a significant loss of mitochondrial membrane potential and increased superoxide anion production and mitochondrial ROS. Also, LEAS induced the arrest of the cell cycle in the G0/G1 phase. Finally, LEAS improved the cytotoxic activity of cisplatin, carboplatin, and in less extension, doxorubicin against the canine osteosarcoma cell line through a synergistic effect. In conclusion, avocado could be a potential source of bioactive molecules in the searching treatments for osteosarcoma. Full article

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23 pages, 6622 KiB

Open AccessArticle

Açai (Euterpe oleracea Mart.) Seed Extract Induces ROS Production and Cell Death in MCF-7 Breast Cancer Cell Line

by Marcos Antonio Custódio Neto da Silva, Jonas Henrique Costa, Taícia Pacheco-Fill, Ana Lúcia Tasca Gois Ruiz, Flávia Castello Branco Vidal, Kátia Regina Assunção Borges, Sulayne Janaina Araújo Guimarães, Ana Paula Silva de Azevedo-Santos, Kaio Eduardo Buglio, Mary Ann Foglio, Maria do Carmo Lacerda Barbosa, Maria do Desterro Soares Brandão Nascimento and João Ernesto de Carvalho

Molecules 2021, 26(12), 3546; https://doi.org/10.3390/molecules26123546 - 10 Jun 2021

Cited by 18 | Viewed by 3405

Abstract

Euterpe oleracea Mart. (açai) is a native palm from the Amazon region. There are various chemical constituents of açai with bioactive properties. This study aimed to evaluate the chemical composition and cytotoxic effects of açai seed extract on breast cancer cell line (MCF-7). [...] Read more.

Euterpe oleracea Mart. (açai) is a native palm from the Amazon region. There are various chemical constituents of açai with bioactive properties. This study aimed to evaluate the chemical composition and cytotoxic effects of açai seed extract on breast cancer cell line (MCF-7). Global Natural Products Social Molecular Networking (GNPS) was applied to identify chemical compounds present in açai seed extract. LC-MS/MS and molecular networking were employed to detect the phenolic compounds of açai. The antioxidant activity of açai seed extract was measured by DPPH assay. MCF-7 breast cancer cell line viability was evaluated by MTT assay. Cell death was evaluated by flow cytometry and time-lapse microscopy. Autophagy was evaluated by orange acridin immunofluorescence assay. Reactive oxygen species (ROS) production was evaluated by DAF assay. From the molecular networking, fifteen compounds were identified, mainly phenolic compounds. The açai seed extract showed cytotoxic effects against MCF-7, induced morphologic changes in the cell line by autophagy and increased the ROS production pathway. The present study suggests that açai seed extract has a high cytotoxic capacity and may induce autophagy by increasing ROS production in breast cancer. Apart from its antioxidant activity, flavonoids with high radical scavenging activity present in açai also generated NO (nitric oxide), contributing to its cytotoxic effect and autophagy induction. Full article

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2020

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12 pages, 2155 KiB

Open AccessCommunication

Broussoflavonol B from Broussonetia kazinoki Siebold Exerts Anti-Pancreatic Cancer Activity through Downregulating FoxM1

by Ji Hye Jeong and Jae-Ha Ryu

Molecules 2020, 25(10), 2328; https://doi.org/10.3390/molecules25102328 - 16 May 2020

Cited by 9 | Viewed by 2534

Abstract

Pancreatic cancer has a high mortality rate due to poor rates of early diagnosis. One tumor suppressor gene in particular, p53, is frequently mutated in pancreatic cancer, and mutations in p53 can inactivate normal wild type p53 activity and increase expression of transcription [...] Read more.

Pancreatic cancer has a high mortality rate due to poor rates of early diagnosis. One tumor suppressor gene in particular, p53, is frequently mutated in pancreatic cancer, and mutations in p53 can inactivate normal wild type p53 activity and increase expression of transcription factor forkhead box M1 (FoxM1). Overexpression of FoxM1 accelerates cellular proliferation and cancer progression. Therefore, inhibition of FoxM1 represents a therapeutic strategy for treating pancreatic cancer. Broussoflavonol B (BF-B), isolated from the stem bark of Broussonetia kazinoki Siebold has previously been shown to inhibit the growth of breast cancer cells. This study aimed to investigate whether BF-B exhibits anti-pancreatic cancer activity and if so, identify the underlying mechanism. BF-B reduced cell proliferation, induced cell cycle arrest, and inhibited cell migration and invasion of human pancreatic cancer PANC-1 cells (p53 mutated). Interestingly, BF-B down-regulated FoxM1 expression at both the mRNA and protein level. It also suppressed the expression of FoxM1 downstream target genes, such as cyclin D1, cyclin B1, and survivin. Cell cycle analysis showed that BF-B induced the arrest of G0/G1 phase. BF-B reduced the phosphorylation of extracellular signal-regulated kinase ½ (ERK½) and expression of ERK½ downstream effector c-Myc, which regulates cell proliferation. Furthermore, BF-B inhibited cell migration and invasion, which are downstream functional properties of FoxM1. These results suggested that BF-B could repress pancreatic cancer cell proliferation by inactivation of the ERK/c-Myc/FoxM1 signaling pathway. Broussoflavonol B from Broussonetia kazinoki Siebold may represent a novel chemo-therapeutic agent for pancreatic cancer. Full article

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18 pages, 4273 KiB

Open AccessArticle

Mustard Seed (Brassica nigra) Extract Exhibits Antiproliferative Effect against Human Lung Cancer Cells through Differential Regulation of Apoptosis, Cell Cycle, Migration, and Invasion

by Asmaa Gamal Ahmed, Usama Khamis Hussein, Amr E. Ahmed, Kyoung Min Kim, Hamada M. Mahmoud, Ola Hammouda, Kyu Yun Jang and Anupam Bishayee

Molecules 2020, 25(9), 2069; https://doi.org/10.3390/molecules25092069 - 29 Apr 2020

Cited by 18 | Viewed by 5784

Abstract

Lung cancer is the primary cause of cancer-related death worldwide, and development of novel lung cancer preventive and therapeutic agents are urgently needed. Brassica nigra (black mustard) seeds are commonly consumed in several Asian and African countries. Mustard seeds previously exhibited significant anticancer [...] Read more.

Lung cancer is the primary cause of cancer-related death worldwide, and development of novel lung cancer preventive and therapeutic agents are urgently needed. Brassica nigra (black mustard) seeds are commonly consumed in several Asian and African countries. Mustard seeds previously exhibited significant anticancer activities against several cancer types. In the present study, we have investigated various cellular and molecular mechanisms of anticancer effects of an ethanolic extract of B. nigra seeds against A549 and H1299 human non-small cell lung cancer cell lines. B. nigra extract showed a substantial growth-inhibitory effect as it reduced the viability and clonogenic survival of A549 and H1299 cells in a concentration-dependent manner. B. nigra extract induced cellular apoptosis in a time- and concentration-dependent fashion as evidenced from increased caspase-3 activity. Furthermore, treatment of both A549 and H1299 cells with B. nigra extract alone or in combination with camptothecin induced DNA double-strand breaks as evidenced by upregulation of γH2A histone family member X, Fanconi anemia group D2 protein, Fanconi anemia group J protein, ataxia-telangiectesia mutated and Rad3-related protein. Based on cell cycle analysis, B. nigra extract significantly arrested A549 and H1299 cells at S and G2/M phases. Additionally, B. nigra extract suppressed the migratory and invasive properties of both cell lines, downregulated the expression of matrix metalloproteinase-2 (MMP2), MMP9, and Snail and upregulated the expression of E-cadherin at mRNA and protein levels. Taken together, these findings indicate that B. nigra seed extract may have an important anticancer potential against human lung cancer which could be mediated through simultaneous and differential regulation of proliferation, apoptosis, DNA damage, cell cycle, migration, and invasion. Full article

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12 pages, 2450 KiB

Open AccessArticle

Polyphenols Extracted from Artemisia annua L. Exhibit Anti-Cancer Effects on Radio-Resistant MDA-MB-231 Human Breast Cancer Cells by Suppressing Stem Cell Phenotype, β-Catenin, and MMP-9

by Young Shin Ko, Eun Joo Jung, Se-il Go, Bae Kwon Jeong, Gon Sup Kim, Jin-Myung Jung, Soon Chan Hong, Choong Won Kim, Hye Jung Kim and Won Sup Lee

Molecules 2020, 25(8), 1916; https://doi.org/10.3390/molecules25081916 - 21 Apr 2020

Cited by 18 | Viewed by 4049

Abstract

Artemisia annua L. has been reported to show anti-cancer activities. Here, we determined whether polyphenols extracted from Artemisia annua L. (pKAL) exhibit anti-cancer effects on radio-resistant MDA-MB-231 human breast cancer cells (RT-R-MDA-MB-231 cells), and further explored their molecular mechanisms. Cell viability assay and [...] Read more.

Artemisia annua L. has been reported to show anti-cancer activities. Here, we determined whether polyphenols extracted from Artemisia annua L. (pKAL) exhibit anti-cancer effects on radio-resistant MDA-MB-231 human breast cancer cells (RT-R-MDA-MB-231 cells), and further explored their molecular mechanisms. Cell viability assay and colony-forming assay revealed that pKAL inhibited cell proliferation on both parental and RT-R-MDA-MB-231 cells in a dose-dependent manner. The anti-proliferative effects of pKAL on RT-R-MDA-MB-231 cells were superior or similar to those on parental ones. Western blot analysis revealed that expressions of cluster of differentiation 44 (CD44) and Oct 3/4, matrix metalloproteinase-9 (MMP-9) and signal transducer and activator of transcription-3 (STAT-3) phosphorylation were significantly increased in RT-R-MDA-MB-231 cells compared to parental ones, suggesting that these proteins could be associated with RT resistance. pKAL inhibited the expression of CD44 and Oct 3/4 (CSC markers), and β-catenin and MMP-9 as well as STAT-3 phosphorylation of RT-R-MDA-MB-231. Regarding upstream signaling, the JNK or JAK2 inhibitor could inhibit STAT-3 activation in RT-R-MDA-MB-231 cells, but not augmented pKAL-induced anti-cancer effects. These findings suggest that c-Jun N-terminal kinase (JNK) or Janus kinase 2 (JAK2)/STAT3 signaling are not closely related to the anti-cancer effects of pKAL. In conclusion, this study suggests that pKAL exhibit anti-cancer effects on RT-R-MDA-MB-231 cells by suppressing CD44 and Oct 3/4, β-catenin and MMP-9, which appeared to be linked to RT resistance of RT-R-MDA-MB-231 cells. Full article

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14 pages, 1713 KiB

Open AccessArticle

Synthesis and In Vitro Anticancer Evaluation of Novel Chrysin and 7-Aminochrysin Derivatives

by Szabolcs Mayer, Péter Keglevich, Péter Ábrányi-Balogh, Áron Szigetvári, Miklós Dékány, Csaba Szántay, Jr. and László Hazai

Molecules 2020, 25(4), 888; https://doi.org/10.3390/molecules25040888 - 17 Feb 2020

Cited by 17 | Viewed by 3785

Abstract

Chrysin is a naturally occurring flavonoid with mild anticancer activity. In this paper we report the synthesis of new chrysin derivatives alkylated with N-phenylchloroacetamides in position 7. A novel method was developed for the preparation of 7-aminochrysin derivatives via the Smiles rearrangement, [...] Read more.

Chrysin is a naturally occurring flavonoid with mild anticancer activity. In this paper we report the synthesis of new chrysin derivatives alkylated with N-phenylchloroacetamides in position 7. A novel method was developed for the preparation of 7-aminochrysin derivatives via the Smiles rearrangement, resulting in diphenylamine-type compounds. In silico studies of the Smiles rearrangement were performed. We also present the in vitro antiproliferative activity of the synthesized compounds against 60 human tumor cell lines (NCI60). The most potent derivative exhibited nanomolar antitumor activity on the MCF7 cell line of breast cancer (GI₅₀ = 30 nM) and on the HCT-15 cell line of colon cancer (GI₅₀ = 60 nM). Full article

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18 pages, 4947 KiB

Open AccessArticle

Berberine Impairs the Survival of Triple Negative Breast Cancer Cells: Cellular and Molecular Analyses

by Lamyae El Khalki, Virginie Maire, Thierry Dubois and Abdelmajid Zyad

Molecules 2020, 25(3), 506; https://doi.org/10.3390/molecules25030506 - 24 Jan 2020

Cited by 23 | Viewed by 4666

Abstract

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. Non-available targeted therapy for TNBC represents its biggest treatment challenge. Thus, finding new promising effective drugs is urgently needed. In the present study, we investigated how berberine, a natural isoquinoline, impairs the [...] Read more.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. Non-available targeted therapy for TNBC represents its biggest treatment challenge. Thus, finding new promising effective drugs is urgently needed. In the present study, we investigated how berberine, a natural isoquinoline, impairs the survival of TNBC cells in both cellular and molecular levels. Our experimental model was based on the use of eight TNBC cell lines: MDA-MB-468, MDA-MB-231, HCC70, HCC38, HCC1937, HCC1143, BT-20, and BT-549. Berberine was cytotoxic against all treated TNBC cell lines. The most sensitive cell lines were HCC70 (IC₅₀ = 0.19 µM), BT-20 (IC₅₀ = 0.23 µM) and MDA-MB-468 (IC₅₀ = 0.48 µM). Using flow cytometry techniques, berberine, at 0.5 and 1 µM for 120 and 144 h, not only induced cell cycle arrest, at G1 and/or G2/M phases, but it also triggered significant apoptosis. At the molecular level, these results are consistent with the expression of their related proteins using Western blot assays. Interestingly, while berberine was cytotoxic against TNBC cells, it had no effect on the viability of normal human breast cells MCF10A cultured in a 3D matrigel model. These results suggest that berberine may be a good potential candidate for TNBC drug development. Full article

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2019

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10 pages, 2437 KiB

Open AccessArticle

Cytotoxicity against HL60 Cells of Ficifolidione Derivatives with Methyl, n-Pentyl, and n-Heptyl Groups

by Hisashi Nishiwaki, Megumi Ikari, Satomi Fujiwara, Kosuke Nishi, Takuya Sugahara, Koichi Akiyama and Satoshi Yamauchi

Molecules 2019, 24(22), 4081; https://doi.org/10.3390/molecules24224081 - 12 Nov 2019

Cited by 2 | Viewed by 2602

Abstract

Ficifolidione, a natural insecticidal compound isolated from the essential oils of Myetaceae species, is a spiro phloroglucinol with an isobutyl group at the C-4 position. We found that ficifolidione showed cytotoxicity against cancer cells via apoptosis. Replacement of the isobutyl group by n [...] Read more.

Ficifolidione, a natural insecticidal compound isolated from the essential oils of Myetaceae species, is a spiro phloroglucinol with an isobutyl group at the C-4 position. We found that ficifolidione showed cytotoxicity against cancer cells via apoptosis. Replacement of the isobutyl group by n-propyl group did not influence the potency, but the effect of the replacement of this group by a shorter or longer alkyl group on the biological activity remains unknown. In this study, ficifolidione derivatives with alkyl groups such as methyl, n-pentyl, and n-heptyl group—instead of the isobutyl group at the C-4 position—were synthesized to evaluate their cytotoxicity against the human promyelocytic leukaemia cell line HL60 and their insecticidal activity against mosquito larvae. The biological activities of their corresponding 4-epimers were also evaluated. As a result, the conversion of the isobutyl group to another alkyl group did not significantly influence the cytotoxicity or insecticidal activity. In HL60 cells treated with the n-heptyl-ficifolidione derivative, the activation of caspase 3/7 and the early stages of apoptosis were detected by using immunofluorescence and flow cytometric techniques, respectively, suggesting that the cytotoxicity should be induced by apoptosis even though the alkyl group was changed. Full article

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15 pages, 4362 KiB

Open AccessArticle

Arnicolide D, from the herb Centipeda minima, Is a Therapeutic Candidate against Nasopharyngeal Carcinoma

by Rui Liu, Brandon Dow Chan, Daniel Kam-Wah Mok, Chi-Sing Lee, William Chi-Shing Tai and Sibao Chen

Molecules 2019, 24(10), 1908; https://doi.org/10.3390/molecules24101908 - 17 May 2019

Cited by 25 | Viewed by 4057

Abstract

Nasopharyngeal carcinoma (NPC) is a high morbidity and mortality cancer with an obvious racial and geographic bias, particularly endemic to Southeast China. Our previous studies demonstrated that Centipeda minima extract (CME) exhibited anti-cancer effects in human NPC cell lines. Arnicolide C and arnicolide [...] Read more.

Nasopharyngeal carcinoma (NPC) is a high morbidity and mortality cancer with an obvious racial and geographic bias, particularly endemic to Southeast China. Our previous studies demonstrated that Centipeda minima extract (CME) exhibited anti-cancer effects in human NPC cell lines. Arnicolide C and arnicolide D are sesquiterpene lactones isolated from Centipeda minima. In this study, for the first time, we investigated their anti-NPC effects and further explored the related molecular mechanisms. The effects of both arnicolide C and arnicolide D were tested in NPC cells CNE-1, CNE-2, SUNE-1, HONE1, and C666-1. The results showed that the two compounds inhibited NPC cell viability in a concentration- and time-dependent manner. As the inhibitory effect of arnicolide D was the more pronounced of the two, our following studies focused on this compound. Arnicolide D could induce cell cycle arrest at G₂/M, and induce cell apoptosis. The molecular mechanism of cell cycle regulation and apoptosis induction was investigated, and the results showed that arnicolide D could downregulate cyclin D3, cdc2, p-PI3K, p-AKT, p-mTOR, and p-STAT3, and upregulate cleaved PARP, cleaved caspase 9, and Bax. Regulation of cyclin B1, cdk6, and Bcl-2 expression by arnicolide D showed dynamic changes according to dose and time. Taken together, arnicolide D modulated the cell cycle, activated the caspase signaling pathway, and inhibited the PI3K/AKT/mTOR and STAT3 signaling pathways. These findings provide a solid base of evidence for arnicolide D as a lead compound for further development, and act as proof for the viability of drug development from traditional Chinese medicines. Full article

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8 pages, 1308 KiB

Open AccessFeature PaperArticle

Anatolicin, a Highly Potent and Selective Cytotoxic Sesquiterpene Coumarin from the Root Extract of Heptaptera anatolica

by Fatma Tosun, John A. Beutler, Tanya T. Ransom and Mahmut Miski

Molecules 2019, 24(6), 1153; https://doi.org/10.3390/molecules24061153 - 23 Mar 2019

Cited by 25 | Viewed by 3214

Abstract

Seven known sesquiterpene coumarins and a new sesquiterpene coumarin, anatolicin (8), were isolated from the dichloromethane extract of the roots of Heptaptera anatolica. Structures of these compounds were elucidated based on their spectral properties. While some of these sesquiterpene coumarins [...] Read more.

Seven known sesquiterpene coumarins and a new sesquiterpene coumarin, anatolicin (8), were isolated from the dichloromethane extract of the roots of Heptaptera anatolica. Structures of these compounds were elucidated based on their spectral properties. While some of these sesquiterpene coumarins showed modest cytotoxic activity against COLO205, KM12, A498, UO31, and TC32 cancer cell lines, selective cytotoxicity of anatolicin (8) and 14′-acetoxybadrakemin (7) were observed at nanomolar level against the UO31 kidney cancer cell line. Full article

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14 pages, 4970 KiB

Open AccessArticle

Aspernolide A Inhibits the Proliferation of Human Laryngeal Carcinoma Cells through the Mitochondrial Apoptotic and STAT3 Signaling Pathways

by Chang Liu, Hong Liu, Yanzhang Wen, Huiqi Huang, Ji Hao, Yibing Lv, Rui Qin and Xinzhou Yang

Molecules 2019, 24(6), 1074; https://doi.org/10.3390/molecules24061074 - 19 Mar 2019

Cited by 17 | Viewed by 3186

Abstract

Aspernolide A, a butyrolactone secondary metabolite, was purified from the endophytic fungus Cladosporium cladosporioides derived from roots of Camptotheca acuminata Decne. In this study, the antitumor activity and mechanisms of aspernolide A on human laryngeal cancer Hep-2 and TU212 cells were studied by [...] Read more.

Aspernolide A, a butyrolactone secondary metabolite, was purified from the endophytic fungus Cladosporium cladosporioides derived from roots of Camptotheca acuminata Decne. In this study, the antitumor activity and mechanisms of aspernolide A on human laryngeal cancer Hep-2 and TU212 cells were studied by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, morphological observation and Western blotting. The results showed that aspernolide A significantly inhibited the proliferation of Hep-2 and TU212 cells in dose- and time-dependent manners. Morphological changes of apoptotic cells could be observed under an inverted microscope, such as irregular margins, decreased adherence ability and chromatin condensation. The expressions of Bax, Caspase-9, Caspase-3 and PARP (poly ADP-ribose polymerase) increased with the increase of dosage while Bcl-2 decreased, suggesting that the apoptotic mechanism might be related to the mitochondrial apoptotic pathway. Moreover, the expression of the phosphorylation of STAT3 decreased with the increase of dosage, suggesting that the apoptotic mechanism might be related to the STAT3 signaling pathway. All these conclusions indicated that aspernolide A has the potential anti-laryngocarcinoma effects. Full article

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19 pages, 292 KiB

Open AccessReview

Anti-Cancer Effects of Green Tea Polyphenols Against Prostate Cancer

by Yasuyoshi Miyata, Yohei Shida, Tomoaki Hakariya and Hideki Sakai

Molecules 2019, 24(1), 193; https://doi.org/10.3390/molecules24010193 - 07 Jan 2019

Cited by 91 | Viewed by 11156

Abstract

Prostate cancer is the most common cancer among men. Green tea consumption is reported to play an important role in the prevention of carcinogenesis in many types of malignancies, including prostate cancer; however, epidemiological studies show conflicting results regarding these anti-cancer effects. In [...] Read more.

Prostate cancer is the most common cancer among men. Green tea consumption is reported to play an important role in the prevention of carcinogenesis in many types of malignancies, including prostate cancer; however, epidemiological studies show conflicting results regarding these anti-cancer effects. In recent years, in addition to prevention, many investigators have shown the efficacy and safety of green tea polyphenols and combination therapies with green tea extracts and anti-cancer agents in in vivo and in vitro studies. Furthermore, numerous studies have revealed the molecular mechanisms of the anti-cancer effects of green tea extracts. We believe that improved understanding of the detailed pathological roles at the molecular level is important to evaluate the prevention and treatment of prostate cancer. Therefore, in this review, we present current knowledge regarding the anti-cancer effects of green tea extracts in the prevention and treatment of prostate cancer, with a particular focus on the molecular mechanisms of action, such as influencing tumor growth, apoptosis, androgen receptor signaling, cell cycle, and various malignant behaviors. Finally, the future direction for the use of green tea extracts as treatment strategies in patients with prostate cancer is introduced. Full article

2018

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15 pages, 2396 KiB

Open AccessArticle

Fucoidan Exerts Anticancer Effects Against Head and Neck Squamous Cell Carcinoma In Vitro

by Wiktoria Blaszczak, Michal Stefan Lach, Wojciech Barczak and Wiktoria Maria Suchorska

Molecules 2018, 23(12), 3302; https://doi.org/10.3390/molecules23123302 - 12 Dec 2018

Cited by 18 | Viewed by 4540

Abstract

Fucoidans have been reported to exert anticancer effects with simultaneous low toxicity against healthy tissue. That correlation was observed in several cancer models, however, it has never been investigated in head and neck cancer before. To magnify the efficacy of conventional therapy, the [...] Read more.

Fucoidans have been reported to exert anticancer effects with simultaneous low toxicity against healthy tissue. That correlation was observed in several cancer models, however, it has never been investigated in head and neck cancer before. To magnify the efficacy of conventional therapy, the administration of agents like fucoidan could be beneficial. The aim of this study was to evaluate the anticancer effect of Fucus vesiculosus (FV) extract alone and with co-administration of cisplatin in head and neck squamous cell carcinoma (HNSCC) in vitro. MTT assay results revealed an FV-induced inhibition of proliferation in all tested cell lines (H103, FaDu, KB). Flow cytometric cell cycle analysis showed an FV-induced, dose-dependent arrest in either S/G2 phase (H103, FaDu) or G1 arrest (KB). Furthermore, a dose-dependent gain in apoptotic fraction was observed. Western blot analysis confirmed the induction of apoptosis. A significant dose-dependent increase in reactive oxygen species (ROS) production was revealed in the H103 cell line, while FaDu cells remained unresponsive. On the contrary, an HPV-positive cell line, KB, demonstrated a dose-dependent decrease in ROS synthesis. Moreover, fucoidan enhanced the response to cisplatin (synergistic effect) in all cell lines with the HPV-positive one (KB) being the most sensitive. These results have been confirmed by flow-cytometric apoptosis analysis. In conclusion, we confirmed that fucoidan exhibits anticancer properties against HNSCC, which are manifested by the induction of apoptosis, regulation of ROS production, cell cycle arrest, and inhibition of proliferation. Full article

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16 pages, 3055 KiB

Open AccessArticle

A Litopenaeus vannamei Hemocyanin-Derived Antimicrobial Peptide (Peptide B11) Attenuates Cancer Cells’ Proliferation

by Shangjie Liu, Jude Juventus Aweya, Liyuan Zheng, Fan Wang, Zhou Zheng, Mingqi Zhong, Jingsheng Lun and Yueling Zhang

Molecules 2018, 23(12), 3202; https://doi.org/10.3390/molecules23123202 - 05 Dec 2018

Cited by 22 | Viewed by 4574

Abstract

Antimicrobial peptides play important roles in the immune response to pathogens and tumor cells; for this reason, they are being exploited for therapeutic use. In this study, we describe a Litopenaeus vannamei hemocyanin-derived peptide, denoted B11, which shares similar features with other anticancer [...] Read more.

Antimicrobial peptides play important roles in the immune response to pathogens and tumor cells; for this reason, they are being exploited for therapeutic use. In this study, we describe a Litopenaeus vannamei hemocyanin-derived peptide, denoted B11, which shares similar features with other anticancer peptides and attenuates the proliferation of cancer cells. Cell viability assay revealed that B11 significantly inhibited the proliferation of human cervical (HeLa), human hepatocellular carcinoma (HepG2), and human esophageal cancer (EC109) cancer cell lines, but not normal liver cell lines (T-antigen-immortalized human liver epithelial (THLE) cells or THLE-3), by inducing morphological changes, nuclear condensation, and margination, features which are indicative of apoptosis. Besides, peptide B11-induced apoptosis was confirmed by isothiocyanate-labeled Annexin V/propidium iodide (Annexin V-FITC/PI) double staining of HeLa cells. Moreover, cell uptake studies, confocal microscopy, and Western blot analysis revealed that rhodamine-labeled B11 permeated HeLa cells and localized to the mitochondria, causing mitochondria dysfunction through lost mitochondrial membrane potential, which consequently triggered the induction of apoptosis. Increased expression levels of caspase-9, caspase-3, and Bax (Bcl-2-associated X) proteins, coupled with a decrease in Bcl-2 (B-cell lymphoma 2) protein, confirmed that peptide B11 induced apoptosis via the mitochondrial pathway. Thus, the hemocyanin-derived peptide, B11, inhibits the proliferation of cancer cells by causing mitochondrial dysfunction and inducing apoptotic cell death, for which reason it could be explored as an anticancer peptide. Full article

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15 pages, 1703 KiB

Open AccessFeature PaperReview

Potential Anti-Inflammatory and Anti-Cancer Properties of Farnesol

by Young Yun Jung, Sun Tae Hwang, Gautam Sethi, Lu Fan, Frank Arfuso and Kwang Seok Ahn

Molecules 2018, 23(11), 2827; https://doi.org/10.3390/molecules23112827 - 31 Oct 2018

Cited by 87 | Viewed by 7851

Abstract

Farnesol, an acyclic sesquiterpene alcohol, is predominantly found in essential oils of various plants in nature. It has been reported to exhibit anti-cancer and anti-inflammatory effects, and also alleviate allergic asthma, gliosis, and edema. In numerous tumor cell lines, farnesol can modulate various [...] Read more.

Farnesol, an acyclic sesquiterpene alcohol, is predominantly found in essential oils of various plants in nature. It has been reported to exhibit anti-cancer and anti-inflammatory effects, and also alleviate allergic asthma, gliosis, and edema. In numerous tumor cell lines, farnesol can modulate various tumorigenic proteins and/or modulates diverse signal transduction cascades. It can also induce apoptosis and downregulate cell proliferation, angiogenesis, and cell survival. To exert its anti-inflammatory/anti-oncogenic effects, farnesol can modulate Ras protein and nuclear factor kappa-light-chain-enhancer of activated B cells activation to downregulate the expression of various inflammatory mediators such as cyclooxygenase-2, inducible nitric oxide synthase, tumor necrosis factor alpha, and interleukin-6. In this review, we describe the potential mechanisms of action underlying the therapeutic effects of farnesol against cancers and inflammatory disorders. Furthermore, these findings support the clinical development of farnesol as a potential pharmacological agent in clinical studies. Full article

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12 pages, 3518 KiB

Open AccessArticle

N-Butanol Subfraction of Brassica Rapa L. Promotes Reactive Oxygen Species Production and Induces Apoptosis of A549 Lung Adenocarcinoma Cells via Mitochondria-Dependent Pathway

by Adila Aipire, Qiuyan Chen, Shanshan Cai, Jinyu Li, Changshuang Fu, Tianlei Ying, Jun Lu and Jinyao Li

Molecules 2018, 23(7), 1687; https://doi.org/10.3390/molecules23071687 - 11 Jul 2018

Cited by 3 | Viewed by 3552

Abstract

Brassica rapa L., an edible and medical vegetable, has been traditionally used in Uyghur folk medicine to treat coughs and asthma in the Xinjiang Uygur Autonomous Region, China. In this study, we prepared an n-butanol subfraction of B. rapa L. (BRBS) [...] Read more.

Brassica rapa L., an edible and medical vegetable, has been traditionally used in Uyghur folk medicine to treat coughs and asthma in the Xinjiang Uygur Autonomous Region, China. In this study, we prepared an n-butanol subfraction of B. rapa L. (BRBS) and investigated the anti-tumor effect on A549 lung adenocarcinoma cells. The proliferation of A549 cells was significantly inhibited by BRBS treatment in a dose- and time-dependent manner. BRBS significantly induced cell cycle arrest and apoptosis in A549 cells through increased reactive oxygen species (ROS) production and mitochondrial dysfunction characterized by a reduction in mitochondrial membrane potential and the release of cytochrome c, which promoted caspase-3 and poly(ADP-ribose) polymerase processing. Moreover, BRBS significantly suppressed the migration of A549 cells in vitro. These results suggest that BRBS inhibited A549 cell proliferation through increased ROS production and the mitochondria-dependent apoptosis pathway. Consequently, BRBS might be a potential candidate for the treatment of lung cancer. Full article

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15 pages, 311 KiB

Open AccessArticle

Antiproliferative and Antimicrobial Activities of Selected Bryophytes

by Martin Vollár, András Gyovai, Péter Szűcs, István Zupkó, Marianna Marschall, Boglárka Csupor-Löffler, Péter Bérdi, Anikó Vecsernyés, Attila Csorba, Erika Liktor-Busa, Edit Urbán and Dezső Csupor

Molecules 2018, 23(7), 1520; https://doi.org/10.3390/molecules23071520 - 23 Jun 2018

Cited by 27 | Viewed by 5068

Abstract

One-hundred and sixty-eight aqueous and organic extracts of 42 selected bryophyte species were screened in vitro for antiproliferative activity on a panel of human gynecological cancer cell lines containing HeLa (cervix epithelial adenocarcinoma), A2780 (ovarian carcinoma), and T47D (invasive ductal breast carcinoma) cells [...] Read more.

One-hundred and sixty-eight aqueous and organic extracts of 42 selected bryophyte species were screened in vitro for antiproliferative activity on a panel of human gynecological cancer cell lines containing HeLa (cervix epithelial adenocarcinoma), A2780 (ovarian carcinoma), and T47D (invasive ductal breast carcinoma) cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and for antibacterial activity on 11 strains using the disc-diffusion method. A total of 99 extracts derived from 41 species exerted ≥25% inhibition of proliferation of at least one of the cancer cell lines at 10 μg/mL. In the cases of Brachythecium rutabulum, Encalypta streptocarpa, Climacium dendroides, Neckera besseri, Pleurozium schreberi, and Pseudoleskeella nervosa, more than one extract was active in the antiproliferative assay, whereas the highest activity was observed in the case of Paraleucobryum longifolium. From the tested families, Brachytheciaceae and Amblystegiaceae provided the highest number of antiproliferative extracts. Only 19 samples of 15 taxa showed moderate antibacterial activity, including the most active Plagiomnium cuspidatum, being active on 8 tested strains. Methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus were the most susceptible to the assayed species. This is the first report on the bioactivities of these 14 species. Full article

6 pages, 1186 KiB

Open AccessArticle

Anticancer Phenolics from Dryopteris fragrans (L.) Schott

by Zhen-Dong Liu, Dan-Dan Zhao, Shuai Jiang, Bei Xue, Yan-Long Zhang and Xiu-Feng Yan

Molecules 2018, 23(3), 680; https://doi.org/10.3390/molecules23030680 - 17 Mar 2018

Cited by 10 | Viewed by 4345

Abstract

Cancer is one of the most major diseases that threatens human health and life. The aim of this work was to obtain novel anticancer molecules from D. fragrans, a kind of medicinal plant. The structure of the new compound was identified using [...] Read more.

Cancer is one of the most major diseases that threatens human health and life. The aim of this work was to obtain novel anticancer molecules from D. fragrans, a kind of medicinal plant. The structure of the new compound was identified using spectroscopic data (¹H-NMR, ¹³C-NMR and two dimensions NMR). Its anticancer properties were evaluated using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay against four human cells including lung cancer cells (A549), breast cancer cells (MCF-7), gastric cancer cells (SGC7901) and noncancerous human umbilical vein endothelial cells (HUVEC). A new phenylpropanoid—(E)-caffeic acid-9-O-β-d-xylpyranosyl-(1→2)-β-d-glucopyranosyl ester (1), with seven known compounds (2–8)—was isolated. The IC₅₀ value of compound 1 against MCF-7 cells was 2.65 ± 0.14 µM, and the IC₅₀ values of compound 8 against three cancer cells were below 20 µM. Full article

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13 pages, 4890 KiB

Open AccessArticle

Antiangiogenic Potential of Microbial Metabolite Elaiophylin for Targeting Tumor Angiogenesis

by Haet Nim Lim, Jun-Pil Jang, Jang Mi Han, Jae-Hyuk Jang, Jong Seog Ahn and Hye Jin Jung

Molecules 2018, 23(3), 563; https://doi.org/10.3390/molecules23030563 - 02 Mar 2018

Cited by 24 | Viewed by 4434

Abstract

Angiogenesis plays a very important role in tumor progression through the creation of new blood vessels. Therefore, angiogenesis inhibitors could contribute to cancer treatment. Here, we show that a microbial metabolite, elaiophylin, exhibits potent antiangiogenic activity from in vitro and in vivo angiogenesis [...] Read more.

Angiogenesis plays a very important role in tumor progression through the creation of new blood vessels. Therefore, angiogenesis inhibitors could contribute to cancer treatment. Here, we show that a microbial metabolite, elaiophylin, exhibits potent antiangiogenic activity from in vitro and in vivo angiogenesis assays. Elaiophylin dramatically suppressed in vitro angiogenic characteristics such as proliferation, migration, adhesion, invasion and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by vascular endothelial growth factor (VEGF) at non-toxic concentrations. In addition, elaiophylin immensely inhibited in vivo angiogenesis of the chorioallantoic membrane (CAM) from growing chick embryos without cytotoxicity. The activation of VEGF receptor 2 (VEGFR2) in HUVECs by VEGF was inhibited by elaiophylin, resulting in the suppression of VEGF-induced activation of downstream signaling molecules, Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, nuclear factor-κB (NFκB), matrix metalloproteinase (MMP)-2 and -9 which are closely associated with VEGF-induced angiogenesis. We also found that elaiophylin blocked tumor cell-induced angiogenesis both in vitro and in vivo. Elaiophylin downregulated the expression of VEGF by inhibiting hypoxia inducible factor-1α (HIF-1α) accumulation in tumor cells. To our knowledge, these results for the first time demonstrate that elaiophylin effectively inhibits angiogenesis and thus may be utilized as a new class of natural antiangiogenic agent for cancer therapy. Full article

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10 pages, 1439 KiB

Open AccessCommunication

Wogonin Suppresses the Activity of Matrix Metalloproteinase-9 and Inhibits Migration and Invasion in Human Hepatocellular Carcinoma

by Ming Hong, Honghui Cheng, Lei Song, Wencai Wang, Qi Wang, Donggang Xu and Weiwei Xing

Molecules 2018, 23(2), 384; https://doi.org/10.3390/molecules23020384 - 11 Feb 2018

Cited by 34 | Viewed by 4796

Abstract

As one of the major active ingredients in Radix Scutellariae, wogonin has been shown to be associated with various pharmacological activities on cancer cell growth, apoptosis, and cell invasion and migration. Here, we demonstrated that wogonin may harbor potential anti-metastatic activities in hepatocarcinoma [...] Read more.

As one of the major active ingredients in Radix Scutellariae, wogonin has been shown to be associated with various pharmacological activities on cancer cell growth, apoptosis, and cell invasion and migration. Here, we demonstrated that wogonin may harbor potential anti-metastatic activities in hepatocarcinoma (HCC). The anti-metastasis potential of wogonin and its underlying mechanisms were evaluated by ligand–protein docking approach, surface plasmon resonance assay, and in vitro gelatin zymography studies. Our results showed that wogonin (100 μM, 50 μM) suppressed MHCC97L and PLC/PRF/5 cells migration and invasion in vitro. The docking approach and surface plasmon resonance assay indicated that the potential binding affinity between wogonin and matrix metalloproteinase-9 (MMP-9) may lead to inhibition of MMP-9 activity and further leads to suppression of tumor metastasis. This conclusion was further verified by Western blot results and gelatin zymography analysis. Wogonin might be a potent treatment option for disrupting the tumor metastasis that favors HCC development. The potential active targets from computational screening integrated with biomedical study may help us to explore the molecular mechanism of herbal medicines. Full article

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15 pages, 3469 KiB

Open AccessArticle

Anti-Tumor and Radiosensitization Effects of N-Butylidenephthalide on Human Breast Cancer Cells

by Yi-Ju Su, Sung-Ying Huang, Yu-Hui Ni, Kuan-Fu Liao and Sheng-Chun Chiu

Molecules 2018, 23(2), 240; https://doi.org/10.3390/molecules23020240 - 25 Jan 2018

Cited by 18 | Viewed by 5233

Abstract

N-Butylidenephthalide (BP), which is extracted from a traditional Chinese medicine, Radix Angelica Sinensis (danggui), displays antitumor activity against various cancer cell lines. The purpose of this study was to investigate the cytotoxic and radiosensitizing effect of BP and the underlying [...] Read more.

N-Butylidenephthalide (BP), which is extracted from a traditional Chinese medicine, Radix Angelica Sinensis (danggui), displays antitumor activity against various cancer cell lines. The purpose of this study was to investigate the cytotoxic and radiosensitizing effect of BP and the underlying mechanism of action in human breast cancer cells. BP induces apoptosis in breast cancer cells, which was revealed by the TUNEL assay; the activation of caspase-9 and PARP was detected by western blot. In addition, BP-induced G2/M arrest was examined by flow cytometry and the expression levels of the G2/M regulatory protein were detected by western blot. BP also suppresses the migration and invasion of breast cancer cells, which was tested by wound healing and the matrigel invasion assay; the involvement of EMT-related gene expressions was detected by real-time PCR. Furthermore, BP enhanced the radiosensitivity of breast cancer cells, which was measured by the colony formation assay and comet assay, where the foci of γ-H2AX after radiation significantly increased in BP pretreated cells and was evidenced by immunocytochemistry staining and western blot. The homologous recombination (HR) repair protein Rad51 was down-regulated after BP pretreatment. These results indicate that BP might be a potential chemotherapeutic and radiosensitizing agent for breast cancer therapy. Full article

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15 pages, 3365 KiB

Open AccessArticle

Curcumin Analog DK1 Induces Apoptosis in Human Osteosarcoma Cells In Vitro through Mitochondria-Dependent Signaling Pathway

by Muhammad Nazirul Mubin Aziz, Yazmin Hussin, Nurul Fattin Che Rahim, Noraini Nordin, Nurul Elyani Mohamad, Swee Keong Yeap, Chean Yeah Yong, Mas Jaffri Masarudin, Yoke Kqueen Cheah, Nadiah Abu, Muhammad Nadeem Akhtar and Noorjahan Banu Alitheen

Molecules 2018, 23(1), 75; https://doi.org/10.3390/molecules23010075 - 05 Jan 2018

Cited by 24 | Viewed by 6609

Abstract

Osteosarcoma is one of the primary malignant bone tumors that confer low survival rates for patients even with intensive regime treatments. Therefore, discovery of novel anti-osteosarcoma drugs derived from natural products that are not harmful to the normal cells remains crucial. Curcumin is [...] Read more.

Osteosarcoma is one of the primary malignant bone tumors that confer low survival rates for patients even with intensive regime treatments. Therefore, discovery of novel anti-osteosarcoma drugs derived from natural products that are not harmful to the normal cells remains crucial. Curcumin is one of the natural substances that have been extensively studied due to its anti-cancer properties and is pharmacologically safe considering its ubiquitous consumption for centuries. However, curcumin suffers from a poor circulating bioavailability, which has led to the development of a chemically synthesized curcuminoid analog, namely (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (DK1). In this study, the cytotoxic effects of the curcumin analog DK1 was investigated in both U-2OS and MG-63 osteosarcoma cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell death was microscopically examined via acridine orange/propidium iodide (AO/PI) double staining. Flow cytometer analysis including Annexin V/Fluorescein isothiocyanate (FITC), cell cycle analysis and JC-1 were adapted to determine the mode of cell death. Subsequently in order to determine the mechanism of cell death, quantitative polymerase chain reaction (qPCR) and proteome profiling was carried out to measure the expression of several apoptotic-related genes and proteins. Results indicated that DK1 induced U-2 OS and MG-63 morphological changes and substantially reduced cell numbers through induction of apoptosis. Several apoptotic genes and proteins were steadily expressed after treatment with DK1; including caspase 3, caspase 9, and BAX, which indicated that apoptosis occurred through a mitochondria-dependent signaling pathway. In conclusion, DK1 could be considered as a potential candidate for an anti-osteosarcoma drug in the near future, contingent upon its ability to induce apoptosis in osteosarcoma cell lines. Full article

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15 pages, 3434 KiB

Open AccessArticle

Cytotoxic Effects and Anti-Angiogenesis Potential of Pistachio (Pistacia vera L.) Hulls against MCF-7 Human Breast Cancer Cells

by Maryam Seifaddinipour, Reyhaneh Farghadani, Farideh Namvar, Jamaludin Mohamad and Habsah Abdul Kadir

Molecules 2018, 23(1), 110; https://doi.org/10.3390/molecules23010110 - 05 Jan 2018

Cited by 29 | Viewed by 6501

Abstract

Pistachio (Pistacia vera L.) hulls (PVLH) represents a significant by-product of industrial pistachio processing that contains high amounta of phenolic and flavonoid compounds known to act as antioxidants. The current study was designed to evaluate the anti-tumor and anti-angiogenic potentials of PVLH [...] Read more.

Pistachio (Pistacia vera L.) hulls (PVLH) represents a significant by-product of industrial pistachio processing that contains high amounta of phenolic and flavonoid compounds known to act as antioxidants. The current study was designed to evaluate the anti-tumor and anti-angiogenic potentials of PVLH extracts. The cytotoxic effects of hexane, ethyl acetate, methanol, and water PVLH extracts toward human colon cancer (HT-29 and HCT-116), breast adenocarcinoma (MCF-7), lung adenocarcinoma (H23), liver hepatocellular carcinoma (HepG2), cervical cancer (Ca Ski), and normal fibroblast (BJ-5ta) cells were assessed using a MTT cell viability assay. Apoptosis induction was evaluated through the different nuclear staining assays and confirmed by flow cytometry analysis. Anti-angiogenic activities were also determined using chorioallantoic membrane (CAM) assay. PVLH ethyl acetate extracts (PVLH-EAE) demonstrated a suppressive effect with an IC₅₀ value of 21.20 ± 1.35, 23.00 ± 1.2 and 25.15 ± 1.85 µg/mL against MCF-7, HT-29 and HCT-116, respectively, after 72 h of treatment. Morphological assessment and flow cytometry analysis showed the potential of PVLH-EAE to induce apoptosis. PVLH-EAE at the highest concentration demonstrated significant inhibition of angiogenesis as comparing with control group. Also the expression of Bax increased and the expression of Bcl-2 decreased in treated MCF-7 cells. Thus, the apoptosis induction and angiogenesis potential of PVLH-EAE make it to be the most suitable for further cancer research study to deal with selective antitumor active substances to human cancers especially breast cancer. Full article

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2017

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1032 KiB

Open AccessArticle

Chemical Constituents from Euphorbia kansui

by Qiao Zhang, Qin-Rong Zhou, Jian-Wei Lou, Pei-Dong Chen, Wei-Feng Yao, Wei-Wei Tao, Yu-Ping Tang, Guan-Cheng Dai, Kun Wang and Li Zhang

Molecules 2017, 22(12), 2176; https://doi.org/10.3390/molecules22122176 - 08 Dec 2017

Cited by 17 | Viewed by 5117

Abstract

In this research, a new triterpenoid, tirucalla-8,24-diene-3β,11β-diol-7-one (1), and eupha-8,24-diene-3β,11β-diol-7-one (2), which was isolated from Euphorbia kansui for the first time, together with twelve other known compounds (3–14), were isolated from the ethyl acetate extract [...] Read more.

In this research, a new triterpenoid, tirucalla-8,24-diene-3β,11β-diol-7-one (1), and eupha-8,24-diene-3β,11β-diol-7-one (2), which was isolated from Euphorbia kansui for the first time, together with twelve other known compounds (3–14), were isolated from the ethyl acetate extract of Euphorbia kansui. Their structures were elucidated based on High resolution electrospray ionization mass spectrometry (HR-ESI-MS), Infrared Spectroscopy (IR), 1D and 2D Nuclear Magnetic Resonance (NMR) data. Both constituents 1 and 2 exhibited moderate cytotoxicity against colon cancer HCT-116, gastric cancer MKN-45 and breast cancer MCF-7. Full article

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2212 KiB

Open AccessReview

Natural Korean Medicine Dang-Gui: Biosynthesis, Effective Extraction and Formulations of Major Active Pyranocoumarins, Their Molecular Action Mechanism in Cancer, and Other Biological Activities

by Chinreddy Subramanyam Reddy, Seong Cheol Kim, Mok Hur, Yeon Bok Kim, Chun Geon Park, Woo Moon Lee, Jae Ki Jang and Sung Cheol Koo

Molecules 2017, 22(12), 2170; https://doi.org/10.3390/molecules22122170 - 07 Dec 2017

Cited by 23 | Viewed by 7050

Abstract

Angelica gigas Nakai (AGN) is a crucial oriental medicinal herb that grows especially in Korea and the Far-East countries. It contains chemically active compounds like pyranocoumarins, polyacetylenes and essential oils, which might be useful for treatment of several chronic diseases. It has been [...] Read more.

Angelica gigas Nakai (AGN) is a crucial oriental medicinal herb that grows especially in Korea and the Far-East countries. It contains chemically active compounds like pyranocoumarins, polyacetylenes and essential oils, which might be useful for treatment of several chronic diseases. It has been used for centuries as a traditional medicine in Southeast Asia, but in Western countries is used as a functional food and a major ingredient of several herbal products. The genus Angelica is also known as ‘female ginseng’ due to its critical therapeutic role in female afflictions, such as gynecological problems. However, it is well-documented that the AGN pyranocoumarins may play vital beneficial roles against cancer, neurodisorders, inflammation, osteoporosis, amnesia, allergies, depression, fungi, diabetes, ischemia, dermatitis, reactive oxygen species (ROS) and androgen. Though numerous studies revealed the role of AGN pyranocoumarins as therapeutic agents, none of the reviews have published their molecular mechanism of action. To the best of our knowledge, this would be the first review that aims to appraise the biosynthesis of AGN’s major active pyranocoumarins, discuss effective extraction and formulation methods, and detail the molecular action mechanism of decursin (D), decursinol angelate (DA) and decursinol (DOH) in chronic diseases, which would further help extension of research in this area. Full article

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1997 KiB

Open AccessArticle

‘Click Chemistry’ Synthesis of Novel Natural Product-Like Caged Xanthones Bearing a 1,2,3-Triazole Moiety with Improved Druglike Properties as Orally Active Antitumor Agents

by Xiang Li, Yue Wu, Yanyan Wang, Qidong You and Xiaojin Zhang

Molecules 2017, 22(11), 1834; https://doi.org/10.3390/molecules22111834 - 27 Oct 2017

Cited by 16 | Viewed by 5178

Abstract

DDO-6101, a natural-product-like caged xanthone discovered previously in our laboratory based on the pharmacophoric scaffold of the Garcinia natural product gambogic acid (GA), shows potent cytotoxicity in vitro, but poor efficacy in vivo due to its poor druglike properties. In order to [...] Read more.

DDO-6101, a natural-product-like caged xanthone discovered previously in our laboratory based on the pharmacophoric scaffold of the Garcinia natural product gambogic acid (GA), shows potent cytotoxicity in vitro, but poor efficacy in vivo due to its poor druglike properties. In order to improve the druglike properties and in vivo antitumor potency, a novel series of ten triazole-bearing caged xanthone derivatives of DDO-6101 has been efficiently synthesized by ‘click chemistry’ and evaluated for their in vitro antitumor activity and druglike properties. Most of the target compounds have sustained cytotoxicity against A549, HepG2, HCT116, and U2OS cancer cells and possess improved aqueous solubility, as well as permeability. Notably, these caged xanthones are also active towards taxol-resistant or cisplatin-resistant A549 cancer cells. Taking both the in vitro activities and druglike properties into consideration, compound 8g has been advanced into in vivo efficacy experiments. The results reveal that 8g (named as DDO-6318), both by intravenous or per os administration, are much more potent than the lead DDO-6101 in A549-transplanted mice models and it could be a promising antitumor candidate for further evaluation. Full article

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Open AccessArticle

Phaseolus acutifolius Lectin Fractions Exhibit Apoptotic Effects on Colon Cancer: Preclinical Studies Using Dimethilhydrazine or Azoxi-Methane as Cancer Induction Agents

by Ulisses Moreno-Celis, Josué López-Martínez, Alejandro Blanco-Labra, Ricardo Cervantes-Jiménez, Laura Elena Estrada-Martínez, Alejandro Eduardo García-Pascalin, María De Jesús Guerrero-Carrillo, Adriana Jheny Rodríguez-Méndez, Carmen Mejía, Roberto Augusto Ferríz-Martínez and Teresa García-Gasca

Molecules 2017, 22(10), 1670; https://doi.org/10.3390/molecules22101670 - 08 Oct 2017

Cited by 21 | Viewed by 5451

Abstract

Phaseolus acutifolius (Tepary bean) lectins have been studied as cytotoxic molecules on colon cancer cells. The toxicological profile of a Tepary bean lectin fraction (TBLF) has shown low toxicity in experimental animals; exhibiting anti-nutritional effects such as a reduction in body weight gain [...] Read more.

Phaseolus acutifolius (Tepary bean) lectins have been studied as cytotoxic molecules on colon cancer cells. The toxicological profile of a Tepary bean lectin fraction (TBLF) has shown low toxicity in experimental animals; exhibiting anti-nutritional effects such as a reduction in body weight gain and a decrease in food intake when using a dose of 50 mg/kg on alternate days for six weeks. Taking this information into account, the focus of this work was to evaluate the effect of the TBLF on colon cancer using 1,2-dimethylhydrazine (DMH) or azoxy-methane/dextran sodium sulfate (AOM/DSS) as colon cancer inductors. Rats were treated with DMH or AOM/DSS and then administered with TBFL (50 mg/kg) for six weeks. TBLF significantly decreased early tumorigenesis triggered by DMH by 70%, but without any evidence of an apoptotic effect. In an independent experiment, AOM/DSS was used to generate aberrant cryptic foci, which decreased by 50% after TBLF treatment. TBLF exhibited antiproliferative and proapoptotic effects related to a decrease of the signal transduction pathway protein Akt in its activated form and an increase of caspase 3 activity, but not to p53 activation. Further studies will deepen our knowledge of specific apoptosis pathways and cellular stress processes such as oxidative damage. Full article

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Open AccessArticle

Therapeutic Mechanisms of Vernonia amygdalina Delile in the Treatment of Prostate Cancer

by William Johnson, Paul B. Tchounwou and Clement G. Yedjou

Molecules 2017, 22(10), 1594; https://doi.org/10.3390/molecules22101594 - 22 Sep 2017

Cited by 17 | Viewed by 7207

Abstract

Prostate cancer patients have been suffering from limited treatment options due to late diagnosis, poor drug tolerance, and multi-drug resistance to almost all the current drug treatments. Therefore, it is important to seek a new alternative therapeutic medicine that can effectively prevent the [...] Read more.

Prostate cancer patients have been suffering from limited treatment options due to late diagnosis, poor drug tolerance, and multi-drug resistance to almost all the current drug treatments. Therefore, it is important to seek a new alternative therapeutic medicine that can effectively prevent the disease and even eradicate the progression and metastasis of prostate cancer. Vernonia amygdalina Delile (VAD) is a common edible vegetable in Cameroon that has been used as a traditional medicine for some human diseases. However, to the best of our knowledge, no previous reports have explored its therapeutic efficacy against human prostate cancer. The objective of the present study was to assess the anticancer activities of VAD methanolic extracts in the prevention and treatment of prostate cancer using human androgen-independent prostate cancer (PC-3) cells as a test model. To achieve our objective, PC-3 cells were treated with various doses of VAD for 48 h. Data generated from the trypan blue test and MTT assay demonstrated that VAD extracts exhibited significant growth-inhibitory effects on PC-3 cells. Collectively, we established for the first time the antiproliferative effects of VAD on PC-3 cells, with an IC₅₀ value of about 196.6 µg/mL. Further experiments, including cell morphology, lipid peroxidation and comet assays, and apoptosis analysis showed that VAD caused growth-inhibitory effects on PC-3 cells through the induction of cell growth arrest, DNA damage, apoptosis, and necrosis in vitro and may provide protection from oxidative stress diseases as a result of its high antioxidant content. These results provide useful data on the anticancer activities of VAD for prostate cancer and demonstrate the novel possibilities of this medicinal plant for developing prostate cancer therapies. Full article

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Open AccessArticle

Polyyne-Enriched Extract from Oplopanax elatus Significantly Ameliorates the Progression of Colon Carcinogenesis in Apc^Min/+ Mice

by Xin Qiao, Wei Sun, Chongzhi Wang, Li Zhang, Ping Li, Xiaodong Wen, Jie Yang and Chunsu Yuan

Molecules 2017, 22(10), 1593; https://doi.org/10.3390/molecules22101593 - 22 Sep 2017

Cited by 10 | Viewed by 4950

Abstract

Colorectal cancer (CRC) is the third most common cancer in the world. Oplopanax elatus is widely used in traditional medicine. However, little is known about its pharmacological effects and bioactive compounds. We evaluated the effects of the polyyne-enriched extract from O. elatus (PEO) [...] Read more.

Colorectal cancer (CRC) is the third most common cancer in the world. Oplopanax elatus is widely used in traditional medicine. However, little is known about its pharmacological effects and bioactive compounds. We evaluated the effects of the polyyne-enriched extract from O. elatus (PEO) on the progression of colon carcinogenesis in Apc^Min/+ mice. In addition, these effects were also investigated in HCT116 and SW480 cells. After PEO oral administration (0.2% diet) for 12 weeks, PEO significantly improved body weight changes and reduced the tumor burden and tumor multiplicity compared with the untreated mice. Meanwhile, western blot and immunohistochemistry results showed PEO significantly reduced the expression of β-catenin and cyclinD1 in both small intestine and the colon tissues compared with the untreated mice. In addition, PEO treatment significant decreased the cell viability in both HCT116 and SW480 cell lines. It also decreased the levels of β-catenin, cyclinD1, c-myc and p-GSK-3β in HCT116 and SW480 cells at 25 μM. These results indicate that PEO may have potential value in prevention of colon cancer by down-regulating Wnt-related protein. Full article

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Open AccessArticle

Cytotoxic and Hypoglycemic Activity of Triterpenoid Saponins from Camellia oleifera Abel. Seed Pomace

by Tai-Mei Di, Shao-Lan Yang, Feng-Yu Du, Lei Zhao, Tao Xia and Xin-Fu Zhang

Molecules 2017, 22(10), 1562; https://doi.org/10.3390/molecules22101562 - 21 Sep 2017

Cited by 36 | Viewed by 5114

Abstract

One new and three known triterpenoid saponins were isolated and identified from Camellia oleifera seeds through IR, NMR, HR-ESI-MS and GC-MS spectroscopic methods, namely oleiferasaponin A₃, oleiferasaponin A₁, camelliasaponin B₁, and camelliasaponin B₂. The structure [...] Read more.

One new and three known triterpenoid saponins were isolated and identified from Camellia oleifera seeds through IR, NMR, HR-ESI-MS and GC-MS spectroscopic methods, namely oleiferasaponin A₃, oleiferasaponin A₁, camelliasaponin B₁, and camelliasaponin B₂. The structure of oleiferasaponin A₃ was elucidated as 16α-hydroxy-21β-O-angeloyl-22α-O-cinnamoyl-23α-aldehyde-28-dihydroxymethylene-olean-12-ene-3β-O-[β-d-galactopyranosyl-(1→2)]-[β-d-xylopyranosyl-(1→2)-β-d-galactopyranosyl-(1→3)]-β-d-gluco-pyranosiduronic acid. Camelliasaponin B₁ and camelliasaponin B₂ exhibited potent cytotoxic activity on three human tumour cell lines (human lung tumour cells (A549), human liver tumour cells (HepG2), cervical tumour cells (Hela)). The hypoglycemic activity of oleiferasaponin A₁ was testified by protecting pancreatic β-cell lines from high-glucose damage. Full article

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Open AccessFeature PaperArticle

Cytotoxic and Apoptotic Activities of Prunus spinosa Trigno Ecotype Extract on Human Cancer Cells

by Stefania Meschini, Evelin Pellegrini, Maria Condello, Giovanni Occhionero, Sebastiano Delfine, Giancarlo Condello and Franco Mastrodonato

Molecules 2017, 22(9), 1578; https://doi.org/10.3390/molecules22091578 - 20 Sep 2017

Cited by 22 | Viewed by 6588

Abstract

The aim of this work was to demonstrate that a natural compound, not-toxic to normal cells, has cytotoxic and sensitizing effects on carcinoma cells, with the final goal of combining it with chemotherapeutic drugs to reduce the overall dose. Prunus spinosa Trigno ecotype [...] Read more.

The aim of this work was to demonstrate that a natural compound, not-toxic to normal cells, has cytotoxic and sensitizing effects on carcinoma cells, with the final goal of combining it with chemotherapeutic drugs to reduce the overall dose. Prunus spinosa Trigno ecotype (PsT) drupe extract with a nutraceutical activator complex (NAC) made of amino acids, vitamins and mineral salt blends, has shown in vitro anticancer activity. The cytotoxic effect of (PsT + NAC)^® has been evaluated on human cancer cells, with an initial screening with colorectal, uterine cervical, and bronchoalveolar cells, and a subsequent focus on colon carcinoma cells HCT116 and SW480. The viability reduction of HCT116 and SW480 after treatment with (PsT 10 mg/mL + NAC)^® was about 40% (p < 0.05), compared to control cells. The cell’s survival reduction was ineffective when the drug vehicle (NAC) was replaced with a phosphate buffer saline (PBS) or physiological solution (PS). The flow cytometry evaluation of cancer cells’ mitochondrial membrane potential showed an increase of 20% depolarized mitochondria. Cell cycle analysis showed a sub G1 (Gap 1 phase) peak appearance (HCT116: 35.1%; SW480: 11.6%), indicating apoptotic cell death induction that was confirmed by Annexin V assay (HCT116: 86%; SW480: 96%). Normal cells were not altered by (PsT + NAC)^® treatments. Full article

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Open AccessArticle

Arenobufagin Induces Apoptotic Cell Death in Human Non-Small-Cell Lung Cancer Cells via the Noxa-Related Pathway

by Liang Ma, Yindi Zhu, Sheng Fang, Hongyan Long, Xiang Liu and Zi Liu

Molecules 2017, 22(9), 1525; https://doi.org/10.3390/molecules22091525 - 11 Sep 2017

Cited by 25 | Viewed by 4863

Abstract

Arenobufagin, an active component isolated from the traditional Chinese medicine Chan Su, exhibits anticancer influences in several human malignancies. However, the effects and action mechanisms of arenobufagin on non-small-cell lung cancer (NSCLC) are still unknown. In this study, we reported that arenobufagin acted [...] Read more.

Arenobufagin, an active component isolated from the traditional Chinese medicine Chan Su, exhibits anticancer influences in several human malignancies. However, the effects and action mechanisms of arenobufagin on non-small-cell lung cancer (NSCLC) are still unknown. In this study, we reported that arenobufagin acted through activation of Noxa-related pathways and promoted apoptotic cell death in human NSCLC cells. Our results revealed that arenobufagin-induced apoptosis was caspase-dependent, as evidenced by the fact that caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP) were cleaved, and pretreatment with a pan-caspase inhibitor Z-VAD-FMK inhibited the pro-apoptosis effect of arenobufagin. Mechanistically, we further found that arenobufagin rapidly upregulated the expression of the pro-apoptosis protein Noxa, and abrogated the anti-apoptosis protein Mcl-1, a major binding partner of Noxa in the cell. More importantly, the knockdown of Noxa greatly blocked arenobufagin-induced cell death, highlighting the contribution of this protein in the anti-NSCLC effects of arenobufagin. Interestingly, arenobufagin also increased the expression of p53, a direct transcriptional activator for the upregulation of the Noxa protein. Taken together, our results suggest that arenobufagin is a potential anti-NSCLC agent that triggers apoptotic cell death in NSCLC cells through interfering with the Noxa-related pathway. Full article

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Open AccessArticle

Ginger Phytochemicals Inhibit Cell Growth and Modulate Drug Resistance Factors in Docetaxel Resistant Prostate Cancer Cell

by Chi-Ming Liu, Chiu-Li Kao, Yu-Ting Tseng, Yi-Ching Lo and Chung-Yi Chen

Molecules 2017, 22(9), 1477; https://doi.org/10.3390/molecules22091477 - 05 Sep 2017

Cited by 55 | Viewed by 7830

Abstract

Ginger has many bioactive compounds with pharmacological activities. However, few studies are known about these bioactive compounds activity in chemoresistant cells. The aim of the present study was to investigate the anticancer properties of ginger phytochemicals in docetaxel-resistant human prostate cancer cells in [...] Read more.

Ginger has many bioactive compounds with pharmacological activities. However, few studies are known about these bioactive compounds activity in chemoresistant cells. The aim of the present study was to investigate the anticancer properties of ginger phytochemicals in docetaxel-resistant human prostate cancer cells in vitro. In this study, we isolated 6-gingerol, 10-gingerol, 4-shogaol, 6-shogaol, 10-shogaol, and 6-dehydrogingerdione from ginger. Further, the antiproliferation activity of these compounds was examined in docetaxel-resistant (PC3R) and sensitive (PC3) human prostate cancer cell lines. 6-gingerol, 10-gingerol, 6-shogaol, and 10-shogaol at the concentration of 100 μM significantly inhibited the proliferation in PC3R but 6-gingerol, 6-shogaol, and 10-shogaol displayed similar activity in PC3. The protein expression of multidrug resistance associated protein 1 (MRP1) and glutathione-S-transferase (GSTπ) is higher in PC3R than in PC3. In summary, we isolated the bioactive compounds from ginger. Our results showed that 6-gingerol, 10-gingerol, 6-shogaol, and 10-shogaol inhibit the proliferation of PC3R cells through the downregulation of MRP1 and GSTπ protein expression. Full article

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Open AccessArticle

Andrographolide Suppresses MV4-11 Cell Proliferation through the Inhibition of FLT3 Signaling, Fatty Acid Synthesis and Cellular Iron Uptake

by Xiao Chen, Jianbin Zhang, Lixia Yuan, Yifei Lay, Yin Kwan Wong, Teck Kwang Lim, Chye Sun Ong, Qingsong Lin, Jigang Wang and Zichun Hua

Molecules 2017, 22(9), 1444; https://doi.org/10.3390/molecules22091444 - 31 Aug 2017

Cited by 14 | Viewed by 7987

Abstract

Background: Andrographolide (ADR), the main active component of Andrographis paniculata, displays anticancer activity in various cancer cell lines, among which leukemia cell lines exhibit the highest sensitivity to ADR. In particular, ADR was also reported to have reduced drug resistance in [...] Read more.

Background: Andrographolide (ADR), the main active component of Andrographis paniculata, displays anticancer activity in various cancer cell lines, among which leukemia cell lines exhibit the highest sensitivity to ADR. In particular, ADR was also reported to have reduced drug resistance in multidrug resistant cell lines. However, the mechanism of action (MOA) of ADR’s anticancer and anti-drug-resistance activities remain elusive. Methods: In this study, we used the MV4-11 cell line, a FLT3 positive acute myeloid leukemia (AML) cell line that displays multidrug resistance, as our experimental system. We first evaluated the effect of ADR on MV4-11 cell proliferation. Then, a quantitative proteomics approach was applied to identify differentially expressed proteins in ADR-treated MV4-11 cells. Finally, cellular processes and signal pathways affected by ADR in MV4-11 cell were predicted with proteomic analysis and validated with in vitro assays. Results: ADR inhibits MV4-11 cell proliferation in a dose- and time-dependent manner. With a proteomic approach, we discovered that ADR inhibited fatty acid synthesis, cellular iron uptake and FLT3 signaling pathway in MV4-11 cells. Conclusions: ADR inhibits MV4-11 cell proliferation through inhibition of fatty acid synthesis, iron uptake and protein synthesis. Furthermore, ADR reduces drug resistance by blocking FLT3 signaling. Full article

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Open AccessArticle

Cytotoxic Activity of Origanum Vulgare L. on Hepatocellular Carcinoma cell Line HepG2 and Evaluation of its Biological Activity

by Hazem S. Elshafie, Maria F. Armentano, Monica Carmosino, Sabino A. Bufo, Vincenzo De Feo and Ippolito Camele

Molecules 2017, 22(9), 1435; https://doi.org/10.3390/molecules22091435 - 30 Aug 2017

Cited by 98 | Viewed by 12294

Abstract

The potential of plant essential oils (EOs) in anticancer treatment has recently received many research efforts to overcome the development of multidrug resistance and their negative side effects. The aims of the current research are to study (i) the cytotoxic effect of the [...] Read more.

The potential of plant essential oils (EOs) in anticancer treatment has recently received many research efforts to overcome the development of multidrug resistance and their negative side effects. The aims of the current research are to study (i) the cytotoxic effect of the crude EO extracted from Origanum vulgare subsp hirtum and its main constituents (carvacrol, thymol, citral and limonene) on hepatocarcinoma HepG2 and healthy human renal cells HEK293; (ii) the antibacterial and phytotoxic activities of the above EO and its main constituents. Results showed that cell viability percentage of treated HepG2 by EO and its main constituents was significantly decreased when compared to untreated cells. The calculated inhibition concentration (IC₅₀) values for HepG2 were lower than healthy renal cells, indicating the sort of selectivity of the studied substances. Citral is not potentially recommended as an anticancer therapeutic agent, since there are no significant differences between IC₅₀ values against both tested cell lines. Results showed also that oregano EO and its main constituents have a significant antibacterial activity and a moderate phytotoxic effect. The current research verified that oregano EO and its main constituents could be potentially utilized as anticancer therapeutic agents. Full article

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Open AccessArticle

Structure Identification and In Vitro Anticancer Activity of Lathyrol-3-phenylacetate-5,15-diacetate

by Jian-ye Zhang, Wen-jing Huang, Hong-mei Sun, Yun Liu, Xiao-qin Zhao, Si-li Tang, Ming-na Sun, Sheng Wang, Jia-jun Li, Ling-ling Zhang, Jun-hua Zhou, Qian-rong Pan and Hu-biao Chen

Molecules 2017, 22(9), 1412; https://doi.org/10.3390/molecules22091412 - 25 Aug 2017

Cited by 9 | Viewed by 5725

Abstract

Natural products from the genus Euphorbia show attention-attracting activities, such as anticancer activity. In this article, classical isolation and structure identification were used in a study on Caper Euphorbia Seed. Subsequently, MTT and wound healing assays, flow cytometry, western blotting, Hoechst 33258 staining [...] Read more.

Natural products from the genus Euphorbia show attention-attracting activities, such as anticancer activity. In this article, classical isolation and structure identification were used in a study on Caper Euphorbia Seed. Subsequently, MTT and wound healing assays, flow cytometry, western blotting, Hoechst 33258 staining and fluorescence microscopy examination were applied to investigate the anticancer activity of the obtained compounds. In a result, lathyrol-3-phenyl- acetate-5,15-diacetate (deoxy Euphorbia factor L1, DEFL1) was isolated from Caper Euphorbia Seed. Moreover, the NMR signals were totally assigned. DEFL1 showed potent inhibition against lung cancer A549 cells, with an IC₅₀ value of 17.51 ± 0.85 μM. Furthermore, DEFL1 suppressed wound healing of A549 cells in a concentration-dependent manner. Mechanically, DEFL1 induced apoptosis, with involvement of an increase of reactive oxygen species (ROS), decrease of mitochondrial membrane potential (ΔΨm), release of cytochrome c, activity raise of caspase-9 and 3. Characteristic features of apoptosis were observed by fluorescence microscopy. In summary, DEFL1 inhibited growth and induced apoptosis in lung cancer A549 cells via a mitochondrial pathway. Full article

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Open AccessArticle

Interaction of Flavonoids from Woodwardia unigemmata with Bovine Serum Albumin (BSA): Application of Spectroscopic Techniques and Molecular Modeling Methods

by Rui Ma, Hong Pan, Tao Shen, Peng Li, Yanan Chen, Zhenyu Li, Xiaxia Di and Shuqi Wang

Molecules 2017, 22(8), 1317; https://doi.org/10.3390/molecules22081317 - 09 Aug 2017

Cited by 15 | Viewed by 6892

Abstract

Phytochemical investigation on the methanol extract of Woodwardia unigemmata resulted in the isolation of seven flavonoids, including one new flavonol acylglycoside (1). The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis and comparison of literature data. [...] Read more.

Phytochemical investigation on the methanol extract of Woodwardia unigemmata resulted in the isolation of seven flavonoids, including one new flavonol acylglycoside (1). The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis and comparison of literature data. The multidrug resistance (MDR) reversing activity was evaluated for the isolated compounds using doxorubicin-resistant K562/A02 cells model. Compound 6 showed comparable MDR reversing effect to verapamil. Furthermore, the interaction between compounds and bovine serum albumin (BSA) was investigated by spectroscopic methods, including steady-state fluorescence, synchronous fluorescence, circular dichroism (CD) spectroscopies, and molecular docking approach. The experimental results indicated that the seven flavonoids bind to BSA by static quenching mechanisms. The negative ΔH and ΔS values indicated that van der Waals interactions and hydrogen bonds contributed in the binding of compounds 2–6 to BSA. In the case of compounds 1 and 7 systems, the hydrophobic interactions play a major role. The binding of compounds to BSA causes slight changes in the secondary structure of BSA. There are two binding sites of compound 6 on BSA and site I is the main site according to the molecular docking studies and the site marker competitive binding assay. Full article

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Open AccessArticle

γ-Tocotrienol Inhibits Proliferation and Induces Apoptosis via the Mitochondrial Pathway in Human Cervical Cancer HeLa Cells

by Weili Xu, Yaqing Mi, Pan He, Shenghua He and Lingling Niu

Molecules 2017, 22(8), 1299; https://doi.org/10.3390/molecules22081299 - 04 Aug 2017

Cited by 31 | Viewed by 6379

Abstract

γ-Tocotrienol, a kind of isoprenoid phytochemical, has antitumor activity. However, there is limited evidence that it has an effect on cervical cancer. In this study, the capacity to inhibit proliferation and induce apoptosis in human cervical cancer HeLa cells and the mechanism underlying [...] Read more.

γ-Tocotrienol, a kind of isoprenoid phytochemical, has antitumor activity. However, there is limited evidence that it has an effect on cervical cancer. In this study, the capacity to inhibit proliferation and induce apoptosis in human cervical cancer HeLa cells and the mechanism underlying these effects were examined. The results indicated that a γ-tocotrienol concentration over 30 μM inhibited the growth of HeLa cells with a 50% inhibitory concentration (IC₅₀) of 46.90 ± 3.50 μM at 24 h, and significantly down-regulated the expression of proliferative cell nuclear antigen (PCNA) and Ki-67. DNA flow cytometric analysis indicated that γ-tocotrienol arrested the cell cycle at G0/G1 phase and reduced the S phase in HeLa cells. γ-tocotrienol induced apoptosis of HeLa cells in a time- and dose-dependent manner. γ-tocotrienol-induced apoptosis in HeLa cells was accompanied by down-regulation of Bcl-2, up-regulation of Bax, release of cytochrome from mitochondria, activation of caspase-9 and caspase-3, and subsequent poly (ADP-ribose) polymerase (PARP) cleavage. These results suggested that γ-tocotrienol could significantly inhibit cell proliferation through G0/G1 cell cycle arrest, and induce apoptosis via the mitochondrial apoptotic pathway in human cervical cancer HeLa cells. Thus, our findings revealed that γ-tocotrienol may be considered as a potential agent for cervical cancer therapy. Full article

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Open AccessArticle

Fisetin Induces Apoptosis Through p53-Mediated Up-Regulation of DR5 Expression in Human Renal Carcinoma Caki Cells

by Kyoung-jin Min, Ju-Ock Nam and Taeg Kyu Kwon

Molecules 2017, 22(8), 1285; https://doi.org/10.3390/molecules22081285 - 02 Aug 2017

Cited by 31 | Viewed by 6493

Abstract

Fisetin is a natural compound found in fruits and vegetables such as strawberries, apples, cucumbers, and onions. Since fisetin can elicit anti-cancer effects, including anti-proliferation and anti-migration, we investigated whether fisetin induced apoptosis in human renal carcinoma (Caki) cells. Fisetin markedly induced sub-G1 [...] Read more.

Fisetin is a natural compound found in fruits and vegetables such as strawberries, apples, cucumbers, and onions. Since fisetin can elicit anti-cancer effects, including anti-proliferation and anti-migration, we investigated whether fisetin induced apoptosis in human renal carcinoma (Caki) cells. Fisetin markedly induced sub-G1 population and cleavage of poly (ADP-ribose) polymerase (PARP), which is a marker of apoptosis, and increased caspase activation. We found that pan-caspase inhibitor (z-VAD-fmk) inhibited fisetin-induced apoptosis. In addition, fisetin induced death receptor 5 (DR5) expression at the transcriptional level, and down-regulation of DR5 by siRNA blocked fisetin-induced apoptosis. Furthermore, fisetin induced p53 protein expression through up-regulation of protein stability, whereas down-regulation of p53 by siRNA markedly inhibited fisetin-induced DR5 expression. In contrast, fisetin induced up-regulation of CHOP expression and reactive oxygen species production, which had no effect on fisetin-induced apoptosis. Taken together, our study demonstrates that fisetin induced apoptosis through p53 mediated up-regulation of DR5 expression at the transcriptional level. Full article

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