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Antitumoral Properties of Natural Products

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 200902

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Guest Editor
Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06126 Perugia, Italy
Interests: cancer chemoprevention; nutrition; olive oil; polyphenols; natural bioactive compounds; antioxidants; oxidative stress; genotoxicity; mutagenicity; apoptosis; cell cycle regulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Cancer is a major public health concern, being one of the main causes of morbidity and mortality worldwide. Carcinogenesis is a complex multistage process in which normal cells trough an alteration of DNA structure/function are transformed into malignant cells acquiring several properties, such as abnormal proliferation and reduced apoptosis. Studies have demonstrated both in vitro and in vivo that many bioactive compounds, from different natural sources, are able to influence a number of pathways related to tumor development. Many different cancer-specific molecular mechanisms and targets have been identified making it possible to use such compounds as alternative therapeutic or adjuvant treatments, or as chemopreventive agents. This Special Issue aims to identify the most recently-discovered new natural bioactive products with anticancer properties and will review their molecular mechanisms of action.

Prof. Dr. Roberto Fabiani
Guest Editor

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Keywords

  • Cancer
  • Chemoprevention
  • Bioactive compounds
  • Natural products
  • DNA damage
  • Apoptosis
  • Proliferation

Published Papers (42 papers)

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Editorial

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7 pages, 235 KiB  
Editorial
Antitumoral Properties of Natural Products
by Roberto Fabiani
Molecules 2020, 25(3), 650; https://doi.org/10.3390/molecules25030650 - 03 Feb 2020
Cited by 13 | Viewed by 2830
Abstract
Cancer is one of the major causes of death worldwide [...] Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)

Research

Jump to: Editorial, Review

16 pages, 3301 KiB  
Article
Coronarin D Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Glioblastoma Cell Line
by Yollanda E. M. Franco, Marcia Y. Okubo, Adriana D. Torre, Paula P. Paiva, Marcela N. Rosa, Viviane A. O. Silva, Rui M. Reis, Ana L. T. G. Ruiz, Paulo M. Imamura, João E. de Carvalho and Giovanna B. Longato
Molecules 2019, 24(24), 4498; https://doi.org/10.3390/molecules24244498 - 09 Dec 2019
Cited by 18 | Viewed by 3899
Abstract
Glioblastoma (GBM) is the most frequent and highest–grade brain tumor in adults. The prognosis is still poor despite the use of combined therapy involving maximal surgical resection, radiotherapy, and chemotherapy. The development of more efficient drugs without noticeable side effects is urgent. Coronarin [...] Read more.
Glioblastoma (GBM) is the most frequent and highest–grade brain tumor in adults. The prognosis is still poor despite the use of combined therapy involving maximal surgical resection, radiotherapy, and chemotherapy. The development of more efficient drugs without noticeable side effects is urgent. Coronarin D is a diterpene obtained from the rhizome extract of Hedychium coronarium, classified as a labdane with several biological activities, principally anticancer potential. The aim of the present study was to determine the anti–cancer properties of Coronarin D in the glioblastoma cell line and further elucidate the underlying molecular mechanisms. Coronarin D potently suppressed cell viability in glioblastoma U–251 cell line, and also induced G1 arrest by reducing p21 protein and histone H2AX phosphorylation, leading to DNA damage and apoptosis. Further studies showed that Coronarin D increased the production of reactive oxygen species, lead to mitochondrial membrane potential depolarization, and subsequently activated caspases and ERK phosphorylation, major mechanisms involved in apoptosis. To our knowledge, this is the first analysis referring to this compound on the glioma cell line. These findings highlight the antiproliferative activity of Coronarin D against glioblastoma cell line U–251 and provide a basis for further investigation on its antineoplastic activity on brain cancer. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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18 pages, 2116 KiB  
Article
Semi-Synthetic Ingenol Derivative from Euphorbia tirucalli Inhibits Protein Kinase C Isotypes and Promotes Autophagy and S-Phase Arrest on Glioma Cell Lines
by Viviane Aline Oliveira Silva, Marcela Nunes Rosa, Aline Tansini, Olga Martinho, Amilcar Tanuri, Adriane Feijó Evangelista, Adriana Cruvinel Carloni, João Paulo Lima, Luiz Francisco Pianowski and Rui Manuel Reis
Molecules 2019, 24(23), 4265; https://doi.org/10.3390/molecules24234265 - 22 Nov 2019
Cited by 6 | Viewed by 2945
Abstract
The identification of signaling pathways that are involved in gliomagenesis is crucial for targeted therapy design. In this study we assessed the biological and therapeutic effect of ingenol-3-dodecanoate (IngC) on glioma. IngC exhibited dose-time-dependent cytotoxic effects on large panel of glioma cell lines [...] Read more.
The identification of signaling pathways that are involved in gliomagenesis is crucial for targeted therapy design. In this study we assessed the biological and therapeutic effect of ingenol-3-dodecanoate (IngC) on glioma. IngC exhibited dose-time-dependent cytotoxic effects on large panel of glioma cell lines (adult, pediatric cancer cells, and primary cultures), as well as, effectively reduced colonies formation. Nevertheless, it was not been able to attenuate cell migration, invasion, and promote apoptotic effects when administered alone. IngC exposure promoted S-phase arrest associated with p21CIP/WAF1 overexpression and regulated a broad range of signaling effectors related to survival and cell cycle regulation. Moreover, IngC led glioma cells to autophagy by LC3B-II accumulation and exhibited increased cytotoxic sensitivity when combined to a specific autophagic inhibitor, bafilomycin A1. In comparison with temozolomide, IngC showed a mean increase of 106-fold in efficacy, with no synergistic effect when they were both combined. When compared with a known compound of the same class, namely ingenol-3-angelate (I3A, Picato®), IngC showed a mean 9.46-fold higher efficacy. Furthermore, IngC acted as a potent inhibitor of protein kinase C (PKC) activity, an emerging therapeutic target in glioma cells, showing differential actions against various PKC isotypes. These findings identify IngC as a promising lead compound for the development of new cancer therapy and they may guide the search for additional PKC inhibitors. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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15 pages, 3419 KiB  
Article
Dicentrine Potentiates TNF-α-Induced Apoptosis and Suppresses Invasion of A549 Lung Adenocarcinoma Cells via Modulation of NF-κB and AP-1 Activation
by Chanatip Ooppachai, Pornngarm Limtrakul (Dejkriengkraikul) and Supachai Yodkeeree
Molecules 2019, 24(22), 4100; https://doi.org/10.3390/molecules24224100 - 13 Nov 2019
Cited by 21 | Viewed by 4180
Abstract
Numerous studies have indicated that tumor necrosis factor-alpha (TNF-α) could induce cancer cell survival and metastasis via activation of transcriptional activity of NF-κB and AP-1. Therefore, the inhibition of TNF-α-induced NF-κB and AP-1 activity has been considered in the search for drugs that [...] Read more.
Numerous studies have indicated that tumor necrosis factor-alpha (TNF-α) could induce cancer cell survival and metastasis via activation of transcriptional activity of NF-κB and AP-1. Therefore, the inhibition of TNF-α-induced NF-κB and AP-1 activity has been considered in the search for drugs that could effectively treat cancer. Dicentrine, an aporphinic alkaloid, exerts anti-inflammatory and anticancer activities. Therefore, we investigated the effects of dicentrine on TNF-α-induced tumor progression in A549 lung adenocarcinoma cells. Our results demonstrated that dicentrine effectively sensitizes TNF-α-induced apoptosis in A549 cells when compared with dicentrine alone. In addition, dicentrine increases caspase-8, -9, -3, and poly (ADP-ribose) polymerase (PARP) activities by upregulating the death-inducing signaling complex and by inhibiting the expression of antiapoptotic proteins including cIAP2, cFLIP, and Bcl-XL. Furthermore, dicentrine inhibits the TNF-α-induced A549 cells invasion and migration. This inhibition is correlated with the suppression of invasive proteins in the presence of dicentrine. Moreover, dicentrine significantly blockes TNF-α-activated TAK1, p38, JNK, and Akt, leading to reduced levels of the transcriptional activity of NF-κB and AP-1. Taken together, our results suggest that dicentrine could enhance TNF-α-induced A549 cell death by inducing apoptosis and reducing cell invasion due to, at least in part, the suppression of TAK-1, MAPK, Akt, AP-1, and NF-κB signaling pathways. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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16 pages, 2804 KiB  
Article
Annona coriacea Mart. Fractions Promote Cell Cycle Arrest and Inhibit Autophagic Flux in Human Cervical Cancer Cell Lines
by Izabela N. Faria Gomes, Renato J. Silva-Oliveira, Viviane A. Oliveira Silva, Marcela N. Rosa, Patrik S. Vital, Maria Cristina S. Barbosa, Fábio Vieira dos Santos, João Gabriel M. Junqueira, Vanessa G. P. Severino, Bruno G Oliveira, Wanderson Romão, Rui Manuel Reis and Rosy Iara Maciel de Azambuja Ribeiro
Molecules 2019, 24(21), 3963; https://doi.org/10.3390/molecules24213963 - 01 Nov 2019
Cited by 10 | Viewed by 3287
Abstract
Plant-based compounds are an option to explore and perhaps overcome the limitations of current antitumor treatments. Annona coriacea Mart. is a plant with a broad spectrum of biological activities, but its antitumor activity is still unclear. The purpose of our study was to [...] Read more.
Plant-based compounds are an option to explore and perhaps overcome the limitations of current antitumor treatments. Annona coriacea Mart. is a plant with a broad spectrum of biological activities, but its antitumor activity is still unclear. The purpose of our study was to determine the effects of A. coriacea fractions on a panel of cervical cancer cell lines and a normal keratinocyte cell line. The antitumor effect was investigated in vitro by viability assays, cell cycle, apoptosis, migration, and invasion assays. Intracellular signaling was assessed by Western blot, and major compounds were identified by mass spectrometry. All fractions exhibited a cytotoxic effect on cisplatin-resistant cell lines, SiHa and HeLa. C3 and C5 were significantly more cytotoxic and selective than cisplatin in SiHa and Hela cells. However, in CaSki, a cisplatin-sensitive cell line, the compounds did not demonstrate higher cytotoxicity when compared with cisplatin. Alkaloids and acetogenins were the main compounds identified in the fractions. These fractions also markedly decreased cell proliferation with p21 increase and cell cycle arrest in G2/M. These effects were accompanied by an increase of H2AX phosphorylation levels and DNA damage index. In addition, fractions C3 and C5 promoted p62 accumulation and decrease of LC3II, as well as acid vesicle levels, indicating the inhibition of autophagic flow. These findings suggest that A. coriacea fractions may become effective antineoplastic drugs and highlight the autophagy inhibition properties of these fractions in sensitizing cervical cancer cells to treatment. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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15 pages, 3989 KiB  
Article
Proanthocyanidin-Rich Fractions from Red Rice Extract Enhance TNF-α-Induced Cell Death and Suppress Invasion of Human Lung Adenocarcinoma Cell A549
by Chayaporn Subkamkaew, Pornngarm Limtrakul (Dejkriengkraikul) and Supachai Yodkeeree
Molecules 2019, 24(18), 3393; https://doi.org/10.3390/molecules24183393 - 18 Sep 2019
Cited by 8 | Viewed by 3826
Abstract
Tumor necrosis factor-alpha (TNF-α) plays a key role in promoting tumor progression, such as stimulation of cell proliferation and metastasis via activation of NF-κB and AP-1. The proanthocyanidin-rich fraction obtained from red rice (PRFR) has been reported for its anti-tumor effects in cancer [...] Read more.
Tumor necrosis factor-alpha (TNF-α) plays a key role in promoting tumor progression, such as stimulation of cell proliferation and metastasis via activation of NF-κB and AP-1. The proanthocyanidin-rich fraction obtained from red rice (PRFR) has been reported for its anti-tumor effects in cancer cells. This study investigated the molecular mechanisms associated with PRFR on cell survival and metastasis of TNF-α-induced A549 human lung adenocarcinoma. Notably, PRFR enhanced TNF-α-induced A549 cell death when compared with PRFP alone and caused a G0-G1 cell cycle arrest. Although, PRFR alone enhanced cell apoptosis, the combination treatment induced the cells that had been enhanced with PRFR and TNF-α to apoptosis that was less than PRFR alone and displayed a partial effect on caspase-8 activation and PARP cleavage. By using the autophagy inhibitor; 3-MA attenuated the effect of how PRFR enhanced TNF-α-induced cell death. This indicates that PRFR not only enhanced TNF-α-induced A549 cell death by apoptotic pathway, but also by induction autophagy. Moreover, PRFR also inhibited TNF-α-induced A549 cell invasion. This effect was associated with PRFR suppressed the TNF-α-induced level of expression for survival, proliferation, and invasive proteins. This was due to reduce of MAPKs, Akt, NF-κB, and AP-1 activation. Taken together, our results suggest that TNF-α-induced A549 cell survival and invasion are attenuated by PRFR through the suppression of the MAPKs, Akt, AP-1, and NF-κB signaling pathways. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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11 pages, 3684 KiB  
Article
CLEFMA Activates the Extrinsic and Intrinsic Apoptotic Processes through JNK1/2 and p38 Pathways in Human Osteosarcoma Cells
by Jia-Sin Yang, Renn-Chia Lin, Yi-Hsien Hsieh, Heng-Hsiung Wu, Geng-Chung Li, Ya-Chiu Lin, Shun-Fa Yang and Ko-Hsiu Lu
Molecules 2019, 24(18), 3280; https://doi.org/10.3390/molecules24183280 - 09 Sep 2019
Cited by 18 | Viewed by 2536
Abstract
Due to the poor prognosis of metastatic osteosarcoma, chemotherapy is usually employed in the adjuvant situation to improve the prognosis and the chances of long-term survival. 4-[3,5-Bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl]-4-oxo-2-butenoic acid (CLEFMA) is a synthetic analog of curcumin and possesses anti-inflammatory and anticancer properties. To further [...] Read more.
Due to the poor prognosis of metastatic osteosarcoma, chemotherapy is usually employed in the adjuvant situation to improve the prognosis and the chances of long-term survival. 4-[3,5-Bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl]-4-oxo-2-butenoic acid (CLEFMA) is a synthetic analog of curcumin and possesses anti-inflammatory and anticancer properties. To further obtain information regarding the apoptotic pathway induced by CLEFMA in osteosarcoma cells, microculture tetrazolium assay, annexin V-FITC/PI apoptosis staining assay, human apoptosis array, and Western blotting were employed. CLEFMA dose-dependently decreased the cell viabilities of human osteosarcoma U2OS and HOS cells and significantly induced apoptosis in human osteosarcoma cells. In addition to the effector caspase 3, CLEFMA significantly activated both extrinsic caspase 8 and intrinsic caspase 9 initiators. Moreover, CLEFMA increased the phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2 and p38. Using inhibitors of JNK (JNK-in-8) and p38 (SB203580), CLEFMA’s increases of cleaved caspases 3, 8, and 9 could be expectedly suppressed, but they could not be affected by co-treatment with the ERK inhibitor (U0126). Conclusively, CLEFMA activates both extrinsic and intrinsic apoptotic pathways in human osteosarcoma cells through JNK and p38 signaling. These findings contribute to a better understanding of the mechanisms responsible for CLEFMA’s apoptotic effects on human osteosarcoma cells. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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16 pages, 2875 KiB  
Article
SB365, Pulsatilla Saponin D Induces Caspase-Independent Cell Death and Augments the Anticancer Effect of Temozolomide in Glioblastoma Multiforme Cells
by Jun-Man Hong, Jin-Hee Kim, Hyemin Kim, Wang Jae Lee and Young-il Hwang
Molecules 2019, 24(18), 3230; https://doi.org/10.3390/molecules24183230 - 05 Sep 2019
Cited by 11 | Viewed by 7217
Abstract
SB365, a saponin D extracted from the roots of Pulsatilla koreana, has been reported to show cytotoxicity in several cancer cell lines. We investigated the effects of SB365 on U87-MG and T98G glioblastoma multiforme (GBM) cells, and its efficacy in combination with [...] Read more.
SB365, a saponin D extracted from the roots of Pulsatilla koreana, has been reported to show cytotoxicity in several cancer cell lines. We investigated the effects of SB365 on U87-MG and T98G glioblastoma multiforme (GBM) cells, and its efficacy in combination with temozolomide for treating GBM. SB365 exerted a cytotoxic effect on GBM cells not by inducing apoptosis, as in other cancer cell lines, but by triggering caspase-independent cell death. Inhibition of autophagic flux and neutralization of the lysosomal pH occurred rapidly after application of SB365, followed by deterioration of mitochondrial membrane potential. A cathepsin B inhibitor and N-acetyl cysteine, an antioxidant, partially recovered cell death induced by SB365. SB365 in combination with temozolomide exerted an additive cytotoxic effect in vitro and in vivo. In conclusion, SB365 inhibits autophagic flux and induces caspase-independent cell death in GBM cells in a manner involving cathepsin B and mainly reactive oxygen species, and its use in combination with temozolomide shows promise for the treatment of GBM. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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14 pages, 3148 KiB  
Article
Diallyl Disulfide Induces Apoptosis and Autophagy in Human Osteosarcoma MG-63 Cells through the PI3K/Akt/mTOR Pathway
by Ziqi Yue, Xin Guan, Rui Chao, Cancan Huang, Dongfang Li, Panpan Yang, Shanshan Liu, Tomoka Hasegawa, Jie Guo and Minqi Li
Molecules 2019, 24(14), 2665; https://doi.org/10.3390/molecules24142665 - 23 Jul 2019
Cited by 51 | Viewed by 7224
Abstract
Diallyl disulfide (DADs), a natural organic compound, is extracted from garlic and scallion and has anti-tumor effects against various tumors. This study investigated the anti-tumor activity of DADs in human osteosarcoma cells and the mechanisms. MG-63 cells were exposed to DADs (0, 20, [...] Read more.
Diallyl disulfide (DADs), a natural organic compound, is extracted from garlic and scallion and has anti-tumor effects against various tumors. This study investigated the anti-tumor activity of DADs in human osteosarcoma cells and the mechanisms. MG-63 cells were exposed to DADs (0, 20, 40, 60, 80, and 100 μM) for different lengths of time (24, 48, and 72 h). The CCK8 assay results showed that DADs inhibited osteosarcoma cell viability in a dose-and time-dependent manner. FITC-Annexin V/propidium iodide staining and flow cytometry demonstrated that the apoptotic ratio increased and the cell cycle was arrested at the G2/M phase as the DADs concentration was increased. A Western blot analysis was employed to detect the levels of caspase-3, Bax, Bcl-2, LC3-II/LC3-I, and p62 as well as suppression of the mTOR pathway. High expression of LC3-II protein revealed that DADs induced formation of autophagosome. Furthermore, DADs-induced apoptosis was weakened after adding 3-methyladenine, demonstrating that the DADs treatment resulted in autophagy-mediated death of MG-63 cells. In addition, DADs depressed p-mTOR kinase activity, and the inhibited PI3K/Akt/mTOR pathway increased DADs-induced apoptosis and autophagy. In conclusion, our results reveal that DADs induced G2/M arrest, apoptosis, and autophagic death of human osteosarcoma cells by inhibiting the PI3K/Akt/mTOR signaling pathway. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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13 pages, 2624 KiB  
Article
13-Ethylberberine Induces Apoptosis through the Mitochondria-Related Apoptotic Pathway in Radiotherapy-Resistant Breast Cancer Cells
by Hana Jin, Young Shin Ko, Sang Won Park, Ki Churl Chang and Hye Jung Kim
Molecules 2019, 24(13), 2448; https://doi.org/10.3390/molecules24132448 - 04 Jul 2019
Cited by 16 | Viewed by 3575
Abstract
Berberine is reported to have multiple biological effects, including antimicrobial, anti-inflammatory, and antitumor activities, and 13-alkyl-substituted berberines show higher activity than berberine against certain bacterial species and human cancer cell lines. In particular, 13-ethylberberine (13-EBR) was reported to have anti-inflammatory effects in endotoxin-activated [...] Read more.
Berberine is reported to have multiple biological effects, including antimicrobial, anti-inflammatory, and antitumor activities, and 13-alkyl-substituted berberines show higher activity than berberine against certain bacterial species and human cancer cell lines. In particular, 13-ethylberberine (13-EBR) was reported to have anti-inflammatory effects in endotoxin-activated macrophage and septic mouse models. Thus, in this study, we aimed to examine the anticancer effects of 13-EBR and its mechanisms in radiotherapy-resistant (RT-R) MDA-MB-231 cells derived from the highly metastatic MDA-MB-231 cells. When we compared the gene expression between MDA-MB-231 and RT-R MDA-MB-231 cells with an RNA microarray, RT-R MDA-MB-231 showed higher levels of anti-apoptotic genes and lower levels of pro-apoptotic genes compared to MDA-MB-231 cells. Accordingly, we examined the effect of 13-EBR on the induction of apoptosis in RT-R MDA-MB-231 and MDA-MB-231 cells. The results showed that 13-EBR reduced the proliferation and colony-forming ability of both MDA-MB-231 and RT-R MDA-MB-231 cells. Moreover, 13-EBR induced apoptosis by promoting both intracellular and mitochondrial reactive oxygen species (ROS) and by regulating the apoptosis-related proteins involved in the intrinsic pathway, not in the extrinsic pathway. These results suggest that 13-EBR has pro-apoptotic effects in RT-R MDA-MB-231 and MDA-MB-231 cells by inducing mitochondrial ROS production and activating the mitochondrial apoptotic pathway, providing useful insights into new potential therapeutic strategies for RT-R breast cancer treatment. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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12 pages, 5038 KiB  
Article
Licochalcone A Suppresses the Proliferation of Osteosarcoma Cells through Autophagy and ATM-Chk2 Activation
by Tai-Shan Shen, Yung-Ken Hsu, Yi-Fu Huang, Hsuan-Ying Chen, Cheng-Pu Hsieh and Chiu-Liang Chen
Molecules 2019, 24(13), 2435; https://doi.org/10.3390/molecules24132435 - 02 Jul 2019
Cited by 29 | Viewed by 3686
Abstract
Licochalcone A, a flavonoid extracted from licorice root, has been shown to exhibit broad anti-inflammatory, anti-bacterial, anticancer, and antioxidative bioactivity. In this study, we investigated the antitumor activity of Licochalcone A against human osteosarcoma cell lines. The data showed that Licochalcone A significantly [...] Read more.
Licochalcone A, a flavonoid extracted from licorice root, has been shown to exhibit broad anti-inflammatory, anti-bacterial, anticancer, and antioxidative bioactivity. In this study, we investigated the antitumor activity of Licochalcone A against human osteosarcoma cell lines. The data showed that Licochalcone A significantly suppressed cell viability in MTT assay and colony formation assay in osteosarcoma cell lines. Exposure to Licochalcone A blocked cell cycle progression at the G2/M transition and induced extrinsic apoptotic pathway in osteosarcoma cell lines. Furthermore, we found the Licochalcone A exposure resulted in rapid ATM and Chk2 activation, and high levels of nuclear foci of phosphorylated Chk2 at Thr 68 site in osteosarcoma cell lines. In addition, Licochalcone A exposure significantly induced autophagy in osteosarcoma cell lines. When Licochalcone A-induced autophagy was blocked by the autophagy inhibitor chloroquine, the expression of activated caspase-3 and Annexin V positive cells were reduced, and cell viability was rescued in Licochalcone A-treated osteosarcoma cell lines. These data indicate that the activation of ATM-Chk2 checkpoint pathway and autophagy may contribute to Licochalcone A-induced anti-proliferating effect in osteosarcoma cell lines. Our findings display the possibility that Licochalcone A may serve as a potential therapeutic agent against osteosarcoma. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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14 pages, 1655 KiB  
Article
A Bifunctional Molecule with Lectin and Protease Inhibitor Activities Isolated from Crataeva tapia Bark Significantly Affects Cocultures of Mesenchymal Stem Cells and Glioblastoma Cells
by Camila Ramalho Bonturi, Mariana Cristina Cabral Silva, Helena Motaln, Bruno Ramos Salu, Rodrigo da Silva Ferreira, Fabricio Pereira Batista, Maria Tereza dos Santos Correia, Patrícia Maria Guedes Paiva, Tamara Lah Turnšek and Maria Luiza Vilela Oliva
Molecules 2019, 24(11), 2109; https://doi.org/10.3390/molecules24112109 - 04 Jun 2019
Cited by 13 | Viewed by 3136
Abstract
Currently available drugs for treatment of glioblastoma, the most aggressive brain tumor, remain inefficient, thus a plethora of natural compounds have already been shown to have antimalignant effects. However, these have not been tested for their impact on tumor cells in their microenvironment-simulated [...] Read more.
Currently available drugs for treatment of glioblastoma, the most aggressive brain tumor, remain inefficient, thus a plethora of natural compounds have already been shown to have antimalignant effects. However, these have not been tested for their impact on tumor cells in their microenvironment-simulated cell models, e.g., mesenchymal stem cells in coculture with glioblastoma cell U87 (GB). Mesenchymal stem cells (MSC) chemotactically infiltrate the glioblastoma microenvironment. Our previous studies have shown that bone-marrow derived MSCs impair U87 growth and invasion via paracrine and cell–cell contact-mediated cross-talk. Here, we report on a plant-derived protein, obtained from Crataeva tapia tree Bark Lectin (CrataBL), having protease inhibitory/lectin activities, and demonstrate its effects on glioblastoma cells U87 alone and their cocultures with MSCs. CrataBL inhibited U87 cell invasion and adhesion. Using a simplified model of the stromal microenvironment, i.e., GB/MSC direct cocultures, we demonstrated that CrataBL, when added in increased concentrations, caused cell cycle arrest and decreased cocultured cells’ viability and proliferation, but not invasion. The cocultured cells’ phenotypes were affected by CrataBL via a variety of secreted immunomodulatory cytokines, i.e., G-CSF, GM-CSF, IL-6, IL-8, and VEGF. We hypothesize that CrataBL plays a role by boosting the modulatory effects of MSCs on these glioblastoma cell lines and thus the effects of this and other natural lectins and/or inhibitors would certainly be different in the tumor microenvironment compared to tumor cells alone. We have provided clear evidence that it makes much more sense testing these potential therapeutic adjuvants in cocultures, mimicking heterogeneous tumor–stroma interactions with cancer cells in vivo. As such, CrataBL is suggested as a new candidate to approach adjuvant treatment of this deadly tumor. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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14 pages, 2951 KiB  
Article
Paris Polyphylla Inhibits Colorectal Cancer Cells via Inducing Autophagy and Enhancing the Efficacy of Chemotherapeutic Drug Doxorubicin
by Liang-Tzung Lin, Wu-Ching Uen, Chen-Yen Choong, Yeu-Ching Shi, Bao-Hong Lee, Cheng-Jeng Tai and Chen-Jei Tai
Molecules 2019, 24(11), 2102; https://doi.org/10.3390/molecules24112102 - 03 Jun 2019
Cited by 27 | Viewed by 3957
Abstract
Colorectal cancer is one of the most common cancers worldwide and chemotherapy is the main approach for the treatment of advanced and recurrent cases. Developing an effective complementary therapy could help to improve tumor suppression efficiency and control adverse effects from chemotherapy. Paris [...] Read more.
Colorectal cancer is one of the most common cancers worldwide and chemotherapy is the main approach for the treatment of advanced and recurrent cases. Developing an effective complementary therapy could help to improve tumor suppression efficiency and control adverse effects from chemotherapy. Paris polyphylla is a folk medicine for treating various forms of cancer, but its effect on colorectal cancer is largely unexplored. The aim of the present study is to investigate the tumor suppression efficacy and the mechanism of action of the ethanolic extract from P. polyphylla (EEPP) in DLD-1 human colorectal carcinoma cells and to evaluate its combined effect with chemotherapeutic drug doxorubicin. The data indicated that EEPP induced DLD-1 cell death via the upregulation of the autophagy markers, without triggering p53- and caspase-3-dependent apoptosis. Moreover, EEPP treatment in combination with doxorubicin enhanced cytotoxicity in these tumor cells. Pennogenin 3-O-beta-chacotrioside and polyphyllin VI were isolated from EEPP and identified as the main candidate active components. Our results suggest that EEPP deserves further evaluation for development as complementary chemotherapy for colorectal cancer. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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15 pages, 3768 KiB  
Article
Cytostatic and Cytotoxic Natural Products against Cancer Cell Models
by Taotao Ling, Walter H. Lang, Julie Maier, Marizza Quintana Centurion and Fatima Rivas
Molecules 2019, 24(10), 2012; https://doi.org/10.3390/molecules24102012 - 26 May 2019
Cited by 20 | Viewed by 5952
Abstract
The increasing prevalence of drug resistant and/or high-risk cancers indicate further drug discovery research is required to improve patient outcome. This study outlines a simplified approach to identify lead compounds from natural products against several cancer cell lines, and provides the basis to [...] Read more.
The increasing prevalence of drug resistant and/or high-risk cancers indicate further drug discovery research is required to improve patient outcome. This study outlines a simplified approach to identify lead compounds from natural products against several cancer cell lines, and provides the basis to better understand structure activity relationship of the natural product cephalotaxine. Using high-throughput screening, a natural product library containing fractions and pure compounds was interrogated for proliferation inhibition in acute lymphoblastic leukemia cellular models (SUP-B15 and KOPN-8). Initial hits were verified in control and counter screens, and those with EC50 values ranging from nanomolar to low micromolar were further characterized via mass spectrometry, NMR, and cytotoxicity measurements. Most of the active compounds were alkaloid natural products including cephalotaxine and homoharringtonine, which were validated as protein synthesis inhibitors with significant potency against several cancer cell lines. A generated BODIPY-cephalotaxine probe provides insight into the mode of action of cephalotaxine and further rationale for its weaker potency when compared to homoharringtonine. The steroidal natural products (ecdysone and muristerone A) also showed modest biological activity and protein synthesis inhibition. Altogether, these findings demonstrate that natural products continue to provide insight into structure and function of molecules with therapeutic potential against drug resistant cancer cell models. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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14 pages, 3341 KiB  
Article
Effect of Cu/Mn-Fortification on In Vitro Activities of the Peptic Hydrolysate of Bovine Lactoferrin against Human Gastric Cancer BGC-823 Cells
by Li-Ying Bo, Tie-Jing Li and Xin-Huai Zhao
Molecules 2019, 24(7), 1195; https://doi.org/10.3390/molecules24071195 - 27 Mar 2019
Cited by 9 | Viewed by 2745
Abstract
Bovine lactoferrin hydrolysate (BLH) was prepared with pepsin, fortified with Cu2+ (Mn2+) 0.64 and 1.28 (0.28 and 0.56) mg/g protein, and then assessed for their activity against human gastric cancer BGC-823 cells. BLH and the four fortified BLH products dose- [...] Read more.
Bovine lactoferrin hydrolysate (BLH) was prepared with pepsin, fortified with Cu2+ (Mn2+) 0.64 and 1.28 (0.28 and 0.56) mg/g protein, and then assessed for their activity against human gastric cancer BGC-823 cells. BLH and the four fortified BLH products dose- and time-dependently had growth inhibition on the cells in both short- and long-time experiments. These samples at dose level of 25 mg/mL could stop cell-cycle progression at the G0/G1-phase, damage mitochondrial membrane, and induce cell apoptosis. In total, the fortified BLH products had higher activities in the cells than BLH alone. Moreover, higher Cu/Mn fortification level brought higher effects, and Mn was more effective than Cu to increase these effects. In the treated cells, the apoptosis-related proteins such as Bad, Bax, p53, cytochrome c, caspase-3, and caspase-9 were up-regulated, while Bcl-2 was down-regulated. Caspase-3 activation was also evidenced using a caspase-3 inhibitor, z-VAD-fmk. Thus, Cu- and especially Mn-fortification of BLH brought health benefits such as increased anti-cancer activity in the BGC-823 cells via activating the apoptosis-related proteins to induce cell apoptosis. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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12 pages, 4440 KiB  
Article
CLE-10 from Carpesium abrotanoides L. Suppresses the Growth of Human Breast Cancer Cells (MDA-MB-231) In Vitro by Inducing Apoptosis and Pro-Death Autophagy Via the PI3K/Akt/mTOR Signaling Pathway
by Li Tian, Fan Cheng, Lei Wang, Wen Qin, Kun Zou and Jianfeng Chen
Molecules 2019, 24(6), 1091; https://doi.org/10.3390/molecules24061091 - 20 Mar 2019
Cited by 20 | Viewed by 3612
Abstract
Background: The antitumor activity of CLE-10 (4-epi-isoinuviscolide), a sesquiterpene lactone compound, isolated from Carpesium abrotanoides L. has rarely been reported. The aim of this study is to investigate the antitumor activity of CLE-10 and give a greater explanation of its underlying mechanisms. Methods: [...] Read more.
Background: The antitumor activity of CLE-10 (4-epi-isoinuviscolide), a sesquiterpene lactone compound, isolated from Carpesium abrotanoides L. has rarely been reported. The aim of this study is to investigate the antitumor activity of CLE-10 and give a greater explanation of its underlying mechanisms. Methods: The cytotoxicity of CLE-10 was evaluated using MTT assay. Autophagy was detected by the formation of mRFP-GFP-LC3 fluorescence puncta and observed using transmission electron microscopy, while flow cytometry was employed to detect apoptosis. The protein expressions were detected through Western blotting. Results: CLE-10 induced pro-death autophagy and apoptosis in MDA-MB-231 cells by increasing the protein expression of LC3-II, p-ULK1, Bax, and Bad, as well as downregulating p-PI3K, p-Akt, p-mTOR, p62, LC3-I, Bcl-2, and Bcl-xl. CLE-10 that was pretreated with 3-methyladenine (3-MA) or chloroquine (CQ) weakened the upregulation of the protein expression of p-ULK1, or the downregulation of p62, p-mTOR, and decreased the level of cytotoxicity against MDA-MB-231 cells. Meanwhile, rapamycin enhanced the effect of CLE-10 on the expression of autophagy-related protein and its cytotoxicity, with the IC50 value of CLE-10 decreasing from 4.07 µM to 2.38 µM. Conclusion: CLE-10 induced pro-death autophagy and apoptosis in MDA-MB-231 cells by upregulating the protein expressions of LC3-II, p-ULK1, Bax, and Bad and downregulating p-PI3K, p-Akt, p-mTOR, p62, Bcl-2, and Bcl-xl. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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25 pages, 4634 KiB  
Article
Antrodin C, an NADPH Dependent Metabolism, Encourages Crosstalk between Autophagy and Apoptosis in Lung Carcinoma Cells by Use of an AMPK Inhibition-Independent Blockade of the Akt/mTOR Pathway
by Hairui Yang, Xu Bai, Henan Zhang, Jingsong Zhang, Yingying Wu, Chuanhong Tang, Yanfang Liu, Yan Yang, Zhendong Liu, Wei Jia and Wenhan Wang
Molecules 2019, 24(5), 993; https://doi.org/10.3390/molecules24050993 - 12 Mar 2019
Cited by 12 | Viewed by 3805
Abstract
The current study aims to explore the possible anti-lung carcinoma activity of ADC as well as the underlying mechanisms by which ADC exerts its actions in NSCLC. Findings showed that ADC potently inhibited the viability of SPCA-1, induced apoptosis triggered by ROS, and [...] Read more.
The current study aims to explore the possible anti-lung carcinoma activity of ADC as well as the underlying mechanisms by which ADC exerts its actions in NSCLC. Findings showed that ADC potently inhibited the viability of SPCA-1, induced apoptosis triggered by ROS, and arrested the cell cycle at the G2/M phase via a P53 signaling pathway. Interestingly, phenomena such as autophagosomes accumulation, conversion of the LC3-I to LC3-II, etc., indicated that autophagy could be activated by ADC. The blockage of autophagy-augmented ADC induced inhibition of cell proliferation, while autophagy activation restored cell death, indicating that autophagy had a protective effect against cell death which was induced by ADC treatment. Meanwhile, ADC treatment suppressed both the Akt/mTOR and AMPK signaling pathways. The joint action of both ADC and the autophagy inhibitor significantly increased the death of SPCA-1. An in vitro phase I metabolic stability assay showed that ADC was highly metabolized in SD rat liver microsomes and moderately metabolized in human liver microsomes, which will assist in predicting the outcomes of clinical pharmacokinetics and toxicity studies. These findings imply that blocking the Akt/mTOR signaling pathway, which was independent of AMPK inhibition, could activate ADC-induced protective autophagy in non-small-cell lung cancer cells. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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13 pages, 4946 KiB  
Article
Bee Venom and Its Peptide Component Melittin Suppress Growth and Migration of Melanoma Cells via Inhibition of PI3K/AKT/mTOR and MAPK Pathways
by Haet Nim Lim, Seung Bae Baek and Hye Jin Jung
Molecules 2019, 24(5), 929; https://doi.org/10.3390/molecules24050929 - 07 Mar 2019
Cited by 51 | Viewed by 6155
Abstract
Malignant melanoma is the deadliest form of skin cancer and highly chemoresistant. Melittin, an amphiphilic peptide containing 26 amino acid residues, is the major active ingredient from bee venom (BV). Although melittin is known to have several biological activities such as anti-inflammatory, antibacterial [...] Read more.
Malignant melanoma is the deadliest form of skin cancer and highly chemoresistant. Melittin, an amphiphilic peptide containing 26 amino acid residues, is the major active ingredient from bee venom (BV). Although melittin is known to have several biological activities such as anti-inflammatory, antibacterial and anticancer effects, its antimelanoma effect and underlying molecular mechanism have not been fully elucidated. In the current study, we investigated the inhibitory effect and action mechanism of BV and melittin against various melanoma cells including B16F10, A375SM and SK-MEL-28. BV and melittin potently suppressed the growth, clonogenic survival, migration and invasion of melanoma cells. They also reduced the melanin formation in α-melanocyte-stimulating hormone (MSH)-stimulated melanoma cells. Furthermore, BV and melittin induced the apoptosis of melanoma cells by enhancing the activities of caspase-3 and -9. In addition, we demonstrated that the antimelanoma effect of BV and melittin is associated with the downregulation of PI3K/AKT/mTOR and MAPK signaling pathways. We also found that the combination of melittin with the chemotherapeutic agent temozolomide (TMZ) significantly increases the inhibition of growth as well as invasion in melanoma cells compared to melittin or TMZ alone. Taken together, these results suggest that melittin could be potentially applied for the prevention and treatment of malignant melanoma. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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14 pages, 2576 KiB  
Article
The Extracts of Artemisia absinthium L. Suppress the Growth of Hepatocellular Carcinoma Cells through Induction of Apoptosis via Endoplasmic Reticulum Stress and Mitochondrial-Dependent Pathway
by Xianxian Wei, Lijie Xia, Dilinigeer Ziyayiding, Qiuyan Chen, Runqing Liu, Xiaoyu Xu and Jinyao Li
Molecules 2019, 24(5), 913; https://doi.org/10.3390/molecules24050913 - 05 Mar 2019
Cited by 14 | Viewed by 3713
Abstract
Artemisia absinthium L. has pharmaceutical and medicinal effects such as antimicrobial, antiparasitic, hepatoprotective, and antioxidant activities. Here, we prepared A. absinthium ethanol extract (AAEE) and its subfractions including petroleum ether (AAEE-Pe) and ethyl acetate (AAEE-Ea) and investigated their antitumor effect on human hepatoma [...] Read more.
Artemisia absinthium L. has pharmaceutical and medicinal effects such as antimicrobial, antiparasitic, hepatoprotective, and antioxidant activities. Here, we prepared A. absinthium ethanol extract (AAEE) and its subfractions including petroleum ether (AAEE-Pe) and ethyl acetate (AAEE-Ea) and investigated their antitumor effect on human hepatoma BEL-7404 cells and mouse hepatoma H22 cells. The cell viability of hepatoma cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The apoptosis, cell cycle, mitochondrial membrane potential (Δψm), and reactive oxygen species (ROS) were analyzed by flow cytometry. The levels of proteins in the cell cycle and apoptotic pathways were detected by Western blot. AAEE, AAEE-Pe, and AAEE-Ea exhibited potent cytotoxicity for both BEL-7404 cells and H22 cells through the induction of cell apoptosis and cell cycle arrest. Moreover, AAEE, AAEE-Pe, and AAEE-Ea significantly reduced Δψm, increased the release of cytochrome c, and promoted the cleavage of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP) in BEL-7404 and H22 cells. AAEE, AAEE-Pe, and AAEE-Ea significantly upregulated the levels of ROS and C/EBP-homologous protein (CHOP). Further, AAEE, AAEE-Pe, and AAEE-Ea significantly inhibited tumor growth in the H22 tumor mouse model and improved the survival of tumor mice without side effects. These results suggest that AAEE, AAEE-Pe, and AAEE-Ea inhibited the growth of hepatoma cells through induction of apoptosis, which might be mediated by the endoplasmic reticulum stress and mitochondrial-dependent pathway. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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15 pages, 1900 KiB  
Article
Cytotoxic Properties of Damiana (Turnera diffusa) Extracts and Constituents and A Validated Quantitative UHPLC-DAD Assay
by Johanna Willer, Karin Jöhrer, Richard Greil, Christian Zidorn and Serhat Sezai Çiçek
Molecules 2019, 24(5), 855; https://doi.org/10.3390/molecules24050855 - 28 Feb 2019
Cited by 15 | Viewed by 6114
Abstract
In our continuing search for new cytotoxic agents, we assayed extracts, fractions, and pure compounds from damiana (Turnera diffusa) against multiple myeloma (NCI-H929, U266, and MM1S) cell lines. After a first liquid-liquid solvent extraction, the ethyl acetate layer of an acetone [...] Read more.
In our continuing search for new cytotoxic agents, we assayed extracts, fractions, and pure compounds from damiana (Turnera diffusa) against multiple myeloma (NCI-H929, U266, and MM1S) cell lines. After a first liquid-liquid solvent extraction, the ethyl acetate layer of an acetone (70%) crude extract was identified as the most active fraction. Further separation of the active fraction led to the isolation of naringenin (1), three apigenin coumaroyl glucosides 24, and five flavone aglycones 59. Naringenin (1) and apigenin 7-O-(4″-O-p-E-coumaroyl)-glucoside (4) showed significant cytotoxic effects against the tested myeloma cell lines. Additionally, we established a validated ultra-high performance liquid chromatography diode array detector (UHPLC-DAD) method for the quantification of the isolated components in the herb and in traditional preparations of T. diffusa. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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18 pages, 7424 KiB  
Article
Cucurbitacin B Induces the Lysosomal Degradation of EGFR and Suppresses the CIP2A/PP2A/Akt Signaling Axis in Gefitinib-Resistant Non-Small Cell Lung Cancer
by Pengfei Liu, Yuchen Xiang, Xuewen Liu, Te Zhang, Rui Yang, Sen Chen, Li Xu, Qingqing Yu, Huzi Zhao, Liang Zhang, Ying Liu and Yuan Si
Molecules 2019, 24(3), 647; https://doi.org/10.3390/molecules24030647 - 12 Feb 2019
Cited by 40 | Viewed by 7350
Abstract
Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation are initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) treatment, but soon develop an acquired resistance. The treatment effect of EGFR-TKIs-resistant NSCLC patients still faces challenges. Cucurbitacin B (CuB), a [...] Read more.
Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation are initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) treatment, but soon develop an acquired resistance. The treatment effect of EGFR-TKIs-resistant NSCLC patients still faces challenges. Cucurbitacin B (CuB), a triterpene hydrocarbon compound isolated from plants of various families and genera, elicits anticancer effects in a variety of cancer types. However, whether CuB is a viable treatment option for gefitinib-resistant (GR) NSCLC remains unclear. Here, we investigated the anticancer effects and underlying mechanisms of CuB. We report that CuB inhibited the growth and invasion of GR NSCLC cells and induced apoptosis. The inhibitory effect of CuB occurred through its promotion of the lysosomal degradation of EGFR and the downregulation of the cancerous inhibitor of protein phosphatase 2A/protein phosphatase 2A/Akt (CIP2A/PP2A/Akt) signaling axis. CuB and cisplatin synergistically inhibited tumor growth. A xenograft tumor model indicated that CuB inhibited tumor growth in vivo. Immunohistochemistry results further demonstrated that CuB decreased EGFR and CIP2A levels in vivo. These findings suggested that CuB could suppress the growth and invasion of GR NSCLC cells by inducing the lysosomal degradation of EGFR and by downregulating the CIP2A/PP2A/Akt signaling axis. Thus, CuB may be a new drug candidate for the treatment of GR NSCLC. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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15 pages, 1603 KiB  
Article
Total Phenols from Grape Leaves Counteract Cell Proliferation and Modulate Apoptosis-Related Gene Expression in MCF-7 and HepG2 Human Cancer Cell Lines
by Selma Ferhi, Sara Santaniello, Sakina Zerizer, Sara Cruciani, Angela Fadda, Daniele Sanna, Antonio Dore, Margherita Maioli and Guy D’hallewin
Molecules 2019, 24(3), 612; https://doi.org/10.3390/molecules24030612 - 10 Feb 2019
Cited by 43 | Viewed by 4813
Abstract
Grape leaves influence several biological activities in the cardiovascular system, acting as antioxidants. In this study, we aimed at evaluating the effect of ethanolic and water extracts from grape leaves grown in Algeria, obtained by accelerator solvent extraction (ASE), on cell proliferation. The [...] Read more.
Grape leaves influence several biological activities in the cardiovascular system, acting as antioxidants. In this study, we aimed at evaluating the effect of ethanolic and water extracts from grape leaves grown in Algeria, obtained by accelerator solvent extraction (ASE), on cell proliferation. The amount of total phenols was determined using the modified Folin-Ciocalteu method, antioxidant activities were evaluated by the 2,2-diphenyl-l-picrylhydrazyl free radical (DPPH*) method and ·OH radical scavenging using electron paramagnetic resonance (EPR) spectroscopy methods. Cell proliferation of HepG2 hepatocarcinoma, MCF-7 human breast cancer cells and vein human umbilical (HUVEC) cells, as control for normal cell growth, was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay (MTT). Apoptosis- related genes were determined by measuring Bax and Bcl-2 mRNA expression levels. Accelerator solvent extractor yield did not show significant difference between the two solvents (ethanol and water) (p > 0.05). Total phenolic content of water and ethanolic extracts was 55.41 ± 0.11 and 155.73 ± 1.20 mg of gallic acid equivalents/g of dry weight, respectively. Ethanolic extracts showed larger amounts of total phenols as compared to water extracts and interesting antioxidant activity. HepG2 and MCF-7 cell proliferation decreased with increasing concentration of extracts (0.5, 1, and 2 mg/mL) added to the culture during a period of 1–72 h. In addition, the expression of the pro-apoptotic gene Bax was increased and that of the anti-apoptotic gene Bcl-2 was decreased in a dose-dependent manner, when both MCF-7 and HepG2 cells were cultured with one of the two extracts for 72 h. None of the extracts elicited toxic effects on vein umbilical HUVEC cells, highlighting the high specificity of the antiproliferative effect, targeting only cancer cells. Finally, our results suggested that ASE crude extract from grape leaves represents a source of bioactive compounds such as phenols, with potential antioxidants activity, disclosing a novel antiproliferative effect affecting only HepG2 and MCF-7 tumor cells. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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16 pages, 2916 KiB  
Article
Liposomal Taro Lectin Nanocapsules Control Human Glioblastoma and Mammary Adenocarcinoma Cell Proliferation
by Anna C. N. T. F. Corrêa, Mauricio A. Vericimo, Andriy Dashevskiy, Patricia R. Pereira and Vania M. F. Paschoalin
Molecules 2019, 24(3), 471; https://doi.org/10.3390/molecules24030471 - 29 Jan 2019
Cited by 22 | Viewed by 4640
Abstract
The search for natural anticancer agents and nanocarrier uses are a part of the current strategies to overcome the side effects caused by chemotherapeutics. Liposomal nanocapsules loaded with purified tarin, a potential immunomodulatory and antitumoral lectin found in taro corms, were produced. Liposomes [...] Read more.
The search for natural anticancer agents and nanocarrier uses are a part of the current strategies to overcome the side effects caused by chemotherapeutics. Liposomal nanocapsules loaded with purified tarin, a potential immunomodulatory and antitumoral lectin found in taro corms, were produced. Liposomes were composed by 1,2-dioleoyl-sn-glycerol-3-phosphoethanolamine, cholesterylhemisuccinate, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[folate(polyethylene glycol)-2000 prepared by thin-film hydration. Small unilamellar vesicles were achieved by sonication and extrusion. Scanning electron microscopy evidenced round-shaped nanocapsules presenting a smooth surface, 150 nm diameter and polydispersity index <0.2, estimated by dynamic light scattering. Tarin entrapment rates were over 80% and leakage of ~3% under 40 days of storage at 4 °C. Entrapped tarin exhibited an 83% release after 6 h at pH 4.6–7.4 and 36 °C. Both free and encapsulated tarin exhibited no in vitro toxicity against healthy mice bone marrow and L929 cells but stimulated the production of fibroblast-like and large round-shaped cells. Encapsulated tarin resulted in inhibition of human glioblastoma (U-87 MG) and breast adenocarcinoma (MDA-MB-231) proliferation, with an IC50 of 39.36 and 71.38 µg/mL, respectively. The effectiveness of encapsulated tarin was similar to conventional chemotherapy drugs, such as cisplatin and temozolide. Tarin liposomal nanocapsules exhibited superior pharmacological activity compared to free tarin as a potential chemotherapy adjuvant. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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14 pages, 3657 KiB  
Article
Phenolic Compounds of Catalpa speciosa, Taxus cuspidata, and Magnolia acuminata have Antioxidant and Anticancer Activity
by Hosam O. Elansary, Agnieszka Szopa, Paweł Kubica, Fahed A. Al-Mana, Eman A. Mahmoud, Tarek K. Ali Zin El-Abedin, Mohamed A. Mattar and Halina Ekiert
Molecules 2019, 24(3), 412; https://doi.org/10.3390/molecules24030412 - 23 Jan 2019
Cited by 39 | Viewed by 4591
Abstract
Tree bark represents an important source of medicinal compounds that may be useful for cancer therapy. In the current study, high-performance liquid chromatography with diode-array detection (HPLC-DAD) was used to determine the profile of the phenolic compounds of Catalpa speciosa, Taxus cuspidata [...] Read more.
Tree bark represents an important source of medicinal compounds that may be useful for cancer therapy. In the current study, high-performance liquid chromatography with diode-array detection (HPLC-DAD) was used to determine the profile of the phenolic compounds of Catalpa speciosa, Taxus cuspidata, and Magnolia acuminata bark extracts. The antioxidant and anticancer bioactivities against different cancer cell lines were investigated. M. acuminata exerted significantly higher antioxidant activities in the diphenyl picrylhydrazine and β-carotene-linoleic acid assays than the other species. In C. speciosa, novel profiles of phenolic acids (ferulic acid was the predominant compound) and catechin were detected. In T. cuspidata, six phenolic acids were detected; the predominant compounds were hydroxycaffeic acid and protocatechuic acid. In M. acuminata, two phenolic acids and three catechins were detected; catechin was the predominant compound. The three species exerted clear anticancer activity against MCF-7, HeLa, Jurkat, T24, and HT-29 cells, with the strongest activity found in the extracts from M. acuminata. No antiproliferative activity against normal cells was found. Flow cytometry revealed greater accumulation of necrotic and early/late apoptotic cells in various treated cancer cells than in untreated control cells, and protocatechuic acid induced a similar accumulation of necrotic cells to that of the bark extracts. Caspase-3 and -7 activity was increased in cancer cells treated with different bark extracts; the highest activity was found in the M. acuminata treatment. Our results suggested that the treatment of cancer cells with bark extracts of M. acuminata, C. speciosa, and T. cuspidata, and protocatechuic acid induced apoptosis, suggesting an association between anticancer activities and individual phenolic compounds. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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12 pages, 3217 KiB  
Article
Evaluating Antitumor and Antioxidant Activities of Yellow Monascus Pigments from Monascus ruber Fermentation
by Hailing Tan, Ziyi Xing, Gong Chen, Xiaofei Tian and Zhenqiang Wu
Molecules 2018, 23(12), 3242; https://doi.org/10.3390/molecules23123242 - 07 Dec 2018
Cited by 40 | Viewed by 3713
Abstract
Yellow Monascus pigments can be of two kinds: Natural and reduced, in which natural yellow Monascus pigments (NYMPs) attract widespread attention for their bioactivities. In this study, the antioxidative and antibreast cancer effects of the water-soluble NYMPs fermented by Monascus ruber CGMCC 10910 [...] Read more.
Yellow Monascus pigments can be of two kinds: Natural and reduced, in which natural yellow Monascus pigments (NYMPs) attract widespread attention for their bioactivities. In this study, the antioxidative and antibreast cancer effects of the water-soluble NYMPs fermented by Monascus ruber CGMCC 10910 were evaluated. Results showed that water-soluble NYMPs had a significantly improved antioxidative activities compared to the reduced yellow Monascus pigments (RYMPs) that were chemically derived from orange or red Monascus pigments. Furthermore, NYMPs exhibited a concentration-dependent inhibition activity on MCF-7 cell growth (p < 0.001). After a 48-h incubation, a 26.52% inhibition yield was determined with 32 μg/mL of NYMPs. NYMPs also significantly inhibited the migration and invasion of MCF-7 cells. Mechanisms of the activities were associated with a down-regulation of the expression of matrix metalloproteinases and vascular endothelial growth factor. Rather than being alternatively used as natural colorants or antioxidants, this work suggested that NYMPs could be selected as potential functional additives in further test of breast cancer prevention and adjuvant therapy. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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14 pages, 9132 KiB  
Article
FAK and S6K1 Inhibitor, Neferine, Dually Induces Autophagy and Apoptosis in Human Neuroblastoma Cells
by Dinh-Chuong Pham, Yu-Chuan Chang, Shian-Ren Lin, Yuh-Ming Fuh, May-Jywan Tsai and Ching-Feng Weng
Molecules 2018, 23(12), 3110; https://doi.org/10.3390/molecules23123110 - 28 Nov 2018
Cited by 25 | Viewed by 3751
Abstract
Human neuroblastoma cancer is the most typical extracranial solid tumor. Yet, new remedial treatment therapies are demanded to overcome its sluggish survival rate. Neferine, isolated from the lotus embryos, inhibits the proliferation of various cancer cells. This study aimed to evaluate the anti-cancer [...] Read more.
Human neuroblastoma cancer is the most typical extracranial solid tumor. Yet, new remedial treatment therapies are demanded to overcome its sluggish survival rate. Neferine, isolated from the lotus embryos, inhibits the proliferation of various cancer cells. This study aimed to evaluate the anti-cancer activity of neferine in IMR32 human neuroblastoma cells and to expose the concealable molecular mechanisms. IMR32 cells were treated with different concentrations of neferine, followed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess cell viability. In an effort to determine the molecular mechanisms in neferine-incubated IMR32 cells, cell cycle arrest, cell migration, and focal adhesion kinase (FAK), the 70-kDa ribosomal S6 kinase 1 (S6K1), poly (ADP-ribose) polymerase (PARP), caspase-3, Beclin-1, and microtubule-associated protein 1A/1B-light chain 3 (LC3) protein expressions were investigated. Neferine strongly disrupted the neuroblastoma cell growth via induction of G2/M phase arrest. Furthermore, neferine provoked autophagy and apoptosis in IMR32 cells, confirmed by p-FAK, and p-S6K1 reduction, LC3-II accumulation, Beclin-1 overexpression, and cleaved caspase-3/PARP improvement. Finally, neferine markedly retarded cell migration of neuroblastoma cancer cells. As a result, our findings for the first time showed an explicit anti-cancer effect of neferine in IMR32 cells, suggesting that neferine might be a potential candidate against human neuroblastoma cells to improve clinical outcomes with further in vivo investigation. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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13 pages, 2104 KiB  
Article
Tumidulin, a Lichen Secondary Metabolite, Decreases the Stemness Potential of Colorectal Cancer Cells
by Yi Yang, Suresh R. Bhosle, Young Hyun Yu, So-Yeon Park, Rui Zhou, İsa Taş, Chathurika D. B. Gamage, Kyung Keun Kim, Iris Pereira, Jae-Seoun Hur, Hyung-Ho Ha and Hangun Kim
Molecules 2018, 23(11), 2968; https://doi.org/10.3390/molecules23112968 - 14 Nov 2018
Cited by 20 | Viewed by 4311
Abstract
Lichens produce various unique chemicals that are used in the pharmaceutical industry. To screen for novel lichen secondary metabolites that inhibit the stemness potential of colorectal cancer cells, we tested acetone extracts of 11 lichen samples collected in Chile. Tumidulin, isolated from Niebla [...] Read more.
Lichens produce various unique chemicals that are used in the pharmaceutical industry. To screen for novel lichen secondary metabolites that inhibit the stemness potential of colorectal cancer cells, we tested acetone extracts of 11 lichen samples collected in Chile. Tumidulin, isolated from Niebla sp., reduced spheroid formation in CSC221, DLD1, and HT29 cells. In addition, mRNA expressions and protein levels of cancer stem markers aldehyde dehydrogenase-1 (ALDH1), cluster of differentiation 133 (CD133), CD44, Lgr5, and Musashi-1 were reduced after tumidulin treatment. Tumidulin decreased the transcriptional activity of the glioma-associated oncogene homolog zinc finger protein (Gli) promoter in reporter assays, and western blotting confirmed decreased Gli1, Gli2, and Smoothened (SMO) protein levels. Moreover, the tumidulin activity was not observed in the presence of Gli and SMO inhibitors. Together, these results demonstrate for the first time that tumidulin is a potent inhibitor of colorectal cancer cell stemness. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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18 pages, 10337 KiB  
Article
Quercetagetin and Patuletin: Antiproliferative, Necrotic and Apoptotic Activity in Tumor Cell Lines
by Jesús J. Alvarado-Sansininea, Luis Sánchez-Sánchez, Hugo López-Muñoz, María L. Escobar, Fernando Flores-Guzmán, Rosario Tavera-Hernández and Manuel Jiménez-Estrada
Molecules 2018, 23(10), 2579; https://doi.org/10.3390/molecules23102579 - 09 Oct 2018
Cited by 37 | Viewed by 6125
Abstract
Quercetagetin and patuletin were extracted by the same method from two different Tagetes species that have multiple uses in folk medicine in Mexico and around the globe, one of which is as an anticancer agent. Their biological activity (IC50 and necrotic, apoptotic [...] Read more.
Quercetagetin and patuletin were extracted by the same method from two different Tagetes species that have multiple uses in folk medicine in Mexico and around the globe, one of which is as an anticancer agent. Their biological activity (IC50 and necrotic, apoptotic and selective activities of these flavonols) was evaluated and compared to that of quercetin, examining specifically the effects of C6 substitution among quercetin, quercetagetin and patuletin. We find that the presence of a methoxyl group in C6 enhances their potency. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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19 pages, 1676 KiB  
Article
Ethylenediamine Derived Carboxamides of Betulinic and Ursolic Acid as Potential Cytotoxic Agents
by Michael Kahnt, Lucie Fischer (née Heller), Ahmed Al-Harrasi and René Csuk
Molecules 2018, 23(10), 2558; https://doi.org/10.3390/molecules23102558 - 08 Oct 2018
Cited by 35 | Viewed by 4209
Abstract
Two easily accessible, natural occurring triterpenoids, betulinic and ursolic acid, were used as starting materials for the synthesis of novel cytotoxic agents. A set of 28 ethylenediamine-spacered carboxamides was prepared holding an additional substituent connected to the ethylenediamine group. The compounds were screened [...] Read more.
Two easily accessible, natural occurring triterpenoids, betulinic and ursolic acid, were used as starting materials for the synthesis of novel cytotoxic agents. A set of 28 ethylenediamine-spacered carboxamides was prepared holding an additional substituent connected to the ethylenediamine group. The compounds were screened in SRB assays to evaluate their cytotoxic activity employing several human tumor cell lines. Betulinic acid-derived carboxamides 1730 showed significantly higher cytotoxicity than their ursolic acid analogs 316. In particular, compounds 25 and 26 were highly cytotoxic, as indicated by EC50 values lower than 1 μM. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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12 pages, 18362 KiB  
Article
Ganoderma tsugae Inhibits the SREBP-1/AR Axis Leading to Suppression of Cell Growth and Activation of Apoptosis in Prostate Cancer Cells
by Shih-Yin Huang, Guan-Jhong Huang, Hsi-Chin Wu, Ming-Ching Kao and Wen-Chin Huang
Molecules 2018, 23(10), 2539; https://doi.org/10.3390/molecules23102539 - 05 Oct 2018
Cited by 17 | Viewed by 4709
Abstract
Recent research suggests that the activation of lipid biosynthesis (lipogenesis) is linked with prostate cancer (PCa) malignancy. Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcriptional regulator controlling lipogenesis. Moreover, androgen receptor (AR) has been well defined to play an important role in [...] Read more.
Recent research suggests that the activation of lipid biosynthesis (lipogenesis) is linked with prostate cancer (PCa) malignancy. Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcriptional regulator controlling lipogenesis. Moreover, androgen receptor (AR) has been well defined to play an important role in lethal PCa aggressiveness from androgen-responsive to castration-resistant status. In this study, we showed that the quality-assured Ganoderma tsugae ethanol extract (GTEE), a Chinese natural and herbal product, significantly inhibited expression of SREBP-1 and its downstream genes associated with lipogenesis in PCa cells. Through inhibiting SREBP-1, GTEE reduced the levels of intracellular fatty acids and lipids in PCa cells. Importantly, GTEE also downregulated the expression of AR and prostate-specific antigen (PSA) in both androgen-responsive and castration-resistant PCa cells. By blocking the SREBP-1/AR axis, GTEE suppressed cell growth and progressive behaviors, as well as activating the caspase-dependent apoptotic pathway in PCa cells. These data provide a new molecular basis of GTEE for the development of a potential therapeutic approach to treat PCa malignancy. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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15 pages, 5411 KiB  
Article
Structural Characterization of Polysaccharides from Dendrobium officinale and Their Effects on Apoptosis of HeLa Cell Line
by Wenxia Yu, Zhiyao Ren, Xiaofeng Zhang, Shangping Xing, Shengchang Tao, Chenxing Liu, Gang Wei, Yuan Yuan and Zhouxi Lei
Molecules 2018, 23(10), 2484; https://doi.org/10.3390/molecules23102484 - 27 Sep 2018
Cited by 47 | Viewed by 4371
Abstract
Dendrobium officinale is a widely used medicinal plant in China with numerous bio-activities. However, the main structure and anti-tumor activity of the polysaccharides from this plant have not been investigated. In this study, we elucidated the main structure of polysaccharides purified with DEAE [...] Read more.
Dendrobium officinale is a widely used medicinal plant in China with numerous bio-activities. However, the main structure and anti-tumor activity of the polysaccharides from this plant have not been investigated. In this study, we elucidated the main structure of polysaccharides purified with DEAE and Sephadex G-25 from Dendrobium officinale grown under different planting conditions. In addition, the anti-tumor activity was tested via MTT assays. The results showed that the polysaccharides of Dendrobium officinale grown under different conditions were almost the same, with slight differences in the branched chain; both polysaccharide fractions consisted of (1→4)-linked mannose and (1→4)-linked glucose, with an O-acetyl group in the mannose. After degradation, the polysaccharide fractions from wild plants showed significant anti-proliferation activity in HeLa cells. The fractions F1 and F3 induced apoptosis by up-regulating the expression of ERK, JNK, and p38. We concluded that polysaccharides from Dendrobium officinale planted in the wild exhibit significant anti-tumor effects only after being degraded to smaller molecular weight species. The planting mode is a significant factor in the pharmacological activity of Dendrobium officinale. We advise that the planting conditions for Dendrobium officinale should be changed. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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13 pages, 1975 KiB  
Article
Microbial Synthesis of Non-Natural Anthraquinone Glucosides Displaying Superior Antiproliferative Properties
by Trang Thi Huyen Nguyen, Ramesh Prasad Pandey, Prakash Parajuli, Jang Mi Han, Hye Jin Jung, Yong Il Park and Jae Kyung Sohng
Molecules 2018, 23(9), 2171; https://doi.org/10.3390/molecules23092171 - 28 Aug 2018
Cited by 8 | Viewed by 4997
Abstract
Anthraquinones, naturally occurring bioactive compounds, have been reported to exhibit various biological activities, including anti-inflammatory, antiviral, antimicrobial, and anticancer effects. In this study, we biotransformed three selected anthraquinones into their novel O-glucoside derivatives, expressing a versatile glycosyltransferase (YjiC) from Bacillus licheniformis DSM [...] Read more.
Anthraquinones, naturally occurring bioactive compounds, have been reported to exhibit various biological activities, including anti-inflammatory, antiviral, antimicrobial, and anticancer effects. In this study, we biotransformed three selected anthraquinones into their novel O-glucoside derivatives, expressing a versatile glycosyltransferase (YjiC) from Bacillus licheniformis DSM 13 in Escherichia coli. Anthraflavic acid, alizarin, and 2-amino-3-hydroxyanthraquinone were exogenously fed to recombinant E. coli as substrate for biotransformation. The products anthraflavic acid-O-glucoside, alizarin 2-O-β-d-glucoside, and 2-amino-3-O-glucosyl anthraquinone produced in the culture broths were characterized by various chromatographic and spectroscopic analyses. The comparative anti-proliferative assay against various cancer cells (gastric cancer-AGS, uterine cervical cancer-HeLa, and liver cancer-HepG2) were remarkable, since the synthesized glucoside compounds showed more than 60% of cell growth inhibition at concentrations ranging from ~50 μM to 100 μM. Importantly, one of the synthesized glucoside derivatives, alizarin 2-O-glucoside inhibited more than 90% of cell growth in all the cancer cell lines tested. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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15 pages, 6534 KiB  
Article
Zeylenone Induces Mitochondrial Apoptosis and Inhibits Migration and Invasion in Gastric Cancer
by Shuxian Yang, Yonghong Liao, Liyong Li, Xudong Xu and Li Cao
Molecules 2018, 23(9), 2149; https://doi.org/10.3390/molecules23092149 - 27 Aug 2018
Cited by 14 | Viewed by 3359
Abstract
The mortality of gastric cancer (GC) is increasing due to its high rates of recurrence and metastasis. Zeylenone (Zey), a type of naturally occurring cyclohexene oxide, was demonstrated to be effective in cancer patients. The aim of this study is to explore the [...] Read more.
The mortality of gastric cancer (GC) is increasing due to its high rates of recurrence and metastasis. Zeylenone (Zey), a type of naturally occurring cyclohexene oxide, was demonstrated to be effective in cancer patients. The aim of this study is to explore the anti-cancer effect of Zey against gastric cancer both in vitro and in vivo, as well as the underlying mechanisms. We found that Zey inhibited gastric tumor growth, as demonstrated by in vitro gastric cancer cell lines and in a human gastric cancer xenograft mouse model. Furthermore, Zey induced substantial apoptosis through a mitochondrial apoptotic pathway, involving mitochondrial transmembrane potential loss, caspase-3 activation, anti-apoptotic protein downregulation, and pro-apoptotic protein upregulation. Notably, we revealed for the first time that Zey suppressed invasion and migration by wound healing and transwell chamber assays. Through Western blotting, we further explored the potential mechanism of Zey’s anti-cancer activity. We found that Zey downregulated the expression of matrix metalloproteinase 2/9 (MMP 2/9) and inhibited the phosphorylation of AKT and ERK. In short, Zey, which induced mitochondrial apoptosis and inhibited proliferation, migration, and invasion, may be developed as a novel drug for the treatment of gastric cancer. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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9 pages, 3897 KiB  
Article
JNK Inactivation Induces Polyploidy and Drug-Resistance in Coronarin D-Treated Osteosarcoma Cells
by Chang-Te Hsu, Yi-Fu Huang, Chen-Pu Hsieh, Chia-Chieh Wu and Tai-Shan Shen
Molecules 2018, 23(9), 2121; https://doi.org/10.3390/molecules23092121 - 23 Aug 2018
Cited by 13 | Viewed by 3034
Abstract
Inhibition of proliferating cells is a critical strategy for cancer therapy. In this study, we demonstrated that coronarin D, a natural component extracted from the rhizomes of Hedychium coronarium, significantly suppressed the proliferation of osteosarcoma cells. The treatment with coronarin D resulted [...] Read more.
Inhibition of proliferating cells is a critical strategy for cancer therapy. In this study, we demonstrated that coronarin D, a natural component extracted from the rhizomes of Hedychium coronarium, significantly suppressed the proliferation of osteosarcoma cells. The treatment with coronarin D resulted in the activation of caspase-3 and apoptosis. This treatment induced the accumulation of cyclin B1 and DNA condensation indicating the treated osteosarcoma cells were arrested in mitotic phase. Furthermore, the treatment with coronarin D increased the levels of phosphorylated c-Jun NH2-terminal kinase (JNK) in human osteosarcoma cells. Pretreatment with JNK inhibitor blocked the accumulation of cyclin B1 and DNA condensation, resulting the accumulation of tetraploid cells in coronarin D-treated osteosarcoma HOS cells, indicating JNK inactivation blocked the mitotic entry and arrested cells in the 4 N state. After adaptation, the arrested tetraploid cells continued to duplicate their DNA resulting in polyploidy. Interestingly, when the arrested mitotic cells induced by coronarin D were treated with JNK inhibitor, the accumulated cyclin B1 and DNA condensation were immediately eliminated. These arrested 4 N cells loss the ability to undergo cytokinesis, and ultimately continued to duplicate DNA upon prolonged arrest resulting in the production of polyploid populations. JNK inactivation, either by the pretreatment with JNK inhibitor or the treatment with JNK inhibitor in coronarin D-induced mitotic cells, both caused resistance to coronarin D-induced cell death. Taken together, our findings indicate that coronarin D induces the apoptosis and mitosis arrest in human osteosarcoma cells. JNK has a crucial role in coronarin D-induced mitosis arrest and apoptosis. We hypothesize that functional evaluation of JNK may produce more specific and effective therapies in coronarin D-related trail for treatment of human osteosarcoma. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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6 pages, 1513 KiB  
Article
Novel Polyketides Produced by the Endophytic Fungus Aspergillus Fumigatus from Cordyceps Sinensis
by Da-Le Guo, Xiao-Hua Li, Dan Feng, Meng-Ying Jin, Yu-Mei Cao, Zhi-Xing Cao, Yu-Cheng Gu, Zhao Geng, Fang Deng and Yun Deng
Molecules 2018, 23(7), 1709; https://doi.org/10.3390/molecules23071709 - 13 Jul 2018
Cited by 7 | Viewed by 4156
Abstract
Five new polyketides, including two pairs of enantiomers and a racemate, were isolated from the fermentation broth of Aspergillus fumigatus, an endophytic fungus isolated from Cordyceps sinensis. Their structures were identified using one-dimensional (1D) and two-dimensional (2D) NMR experiments, and the [...] Read more.
Five new polyketides, including two pairs of enantiomers and a racemate, were isolated from the fermentation broth of Aspergillus fumigatus, an endophytic fungus isolated from Cordyceps sinensis. Their structures were identified using one-dimensional (1D) and two-dimensional (2D) NMR experiments, and the absolute configurations of the enantiomers were confirmed using electronic circular dichroism (ECD) calculations. Compounds 1a and 2a exhibited inhibitory activity against the MV4-11 cell line in vitro, with IC50 values of 23.95 µM and 32.70 µM, respectively. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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11 pages, 2517 KiB  
Article
Cytotoxic Triterpenes from Salacia crassifolia and Metabolite Profiling of Celastraceae Species
by Laila S. Espindola, Renata G. Dusi, Daniel P. Demarque, Raimundo Braz-Filho, Pengcheng Yan, Heidi R. Bokesch, Kirk R. Gustafson and John A. Beutler
Molecules 2018, 23(6), 1494; https://doi.org/10.3390/molecules23061494 - 20 Jun 2018
Cited by 16 | Viewed by 4875
Abstract
The new pentacyclic triterpene 11β-hydroxypristimerin (1), along with the known metabolites pristimerin (2), 6-oxopristimerol (3) and vitideasin (4), were isolated from a Salacia crassifolia root wood extract, following a bioassay-guided fractionation approach. Both [...] Read more.
The new pentacyclic triterpene 11β-hydroxypristimerin (1), along with the known metabolites pristimerin (2), 6-oxopristimerol (3) and vitideasin (4), were isolated from a Salacia crassifolia root wood extract, following a bioassay-guided fractionation approach. Both the extract and the purified triterpenes displayed pronounced cytotoxic activity against human cancer cell lines. The NCI-60 cell line screen revealed that compound 2 was the most active, with a mean GI50 of 0.17 μM, while compound 1 had a mean GI50 of 8.7 μM. A COMPARE analysis of the screening results showed that pristimerin is likely to be the main compound responsible for the cytotoxic activity of the extract (mean GI50 of 0.3 μg·mL−1). A targeted search for pristimerin and related derivatives using LC-MS/MS revealed the presence of pristimerin (2) and 6-oxopristimerol (3) in all Celastraceae species examined and in all plant parts tested, while vitideasin (4) was only detected in the genus Salacia. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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Review

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14 pages, 955 KiB  
Review
Anti-Cancer Activity of Porphyran and Carrageenan from Red Seaweeds
by Zhiwei Liu, Tianheng Gao, Ying Yang, Fanxin Meng, Fengping Zhan, Qichen Jiang and Xian Sun
Molecules 2019, 24(23), 4286; https://doi.org/10.3390/molecules24234286 - 25 Nov 2019
Cited by 91 | Viewed by 9460
Abstract
Seaweeds are some of the largest producers of biomass in the marine environment and are rich in bioactive compounds that are often used for human and animal health. Porphyran and carrageenan are natural compounds derived from red seaweeds. The former is a characteristic [...] Read more.
Seaweeds are some of the largest producers of biomass in the marine environment and are rich in bioactive compounds that are often used for human and animal health. Porphyran and carrageenan are natural compounds derived from red seaweeds. The former is a characteristic polysaccharide of Porphyra, while the latter is well known from Chondrus, Gigartina, and various Eucheuma species, all in Rhodophyceae. The two polysaccharides have been found to have anti-cancer activity by improving immunity and targeting key apoptotic molecules and therefore deemed as potential chemotherapeutic or chemopreventive agents. This review attempts to review the current study of anti-cancer activity and the possible mechanisms of porphyran and carrageenan derived from red seaweeds to various cancers, and their cooperative actions with other anti-cancer chemotherapeutic agents is also discussed. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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12 pages, 2246 KiB  
Review
Structural Modifications of Nature-Inspired Indoloquinolines: A Mini Review of Their Potential Antiproliferative Activity
by Ning Wang, Marta Świtalska, Li Wang, Elkhabiry Shaban, Md Imran Hossain, Ibrahim El Tantawy El Sayed, Joanna Wietrzyk and Tsutomu Inokuchi
Molecules 2019, 24(11), 2121; https://doi.org/10.3390/molecules24112121 - 05 Jun 2019
Cited by 30 | Viewed by 3962
Abstract
Cryptolepine, neocryptolepine and isocryptolepine are naturally occurring indoloquinoline alkaloids with various spectrum of biological properties. Structural modification is an extremely effective means to improve their bioactivities. This review enumerates several neocryptolepine and isocryptolepine analogues with potent antiproliferative activity against MV4-11 (leukemia), A549 (lung [...] Read more.
Cryptolepine, neocryptolepine and isocryptolepine are naturally occurring indoloquinoline alkaloids with various spectrum of biological properties. Structural modification is an extremely effective means to improve their bioactivities. This review enumerates several neocryptolepine and isocryptolepine analogues with potent antiproliferative activity against MV4-11 (leukemia), A549 (lung cancer), HCT116 (colon cancer) cell lines in vitro. Its activity towards normal mouse fibroblasts BALB/3T3 was also evaluated. Furthermore, structure activity relationships (SAR) are briefly discussed. The anticancer screening of neocryptolepine derivatives was performed in order to determine their cytotoxic and growth inhibitory activities across the JFCR39 cancer cell line panel. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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14 pages, 1158 KiB  
Review
Pleiotropic Pharmacological Actions of Capsazepine, a Synthetic Analogue of Capsaicin, against Various Cancers and Inflammatory Diseases
by Min Hee Yang, Sang Hoon Jung, Gautam Sethi and Kwang Seok Ahn
Molecules 2019, 24(5), 995; https://doi.org/10.3390/molecules24050995 - 12 Mar 2019
Cited by 43 | Viewed by 6406
Abstract
Capsazepine is a synthetic analogue of capsaicin that can function as an antagonist of TRPV1. Capsazepine can exhibit diverse effects on cancer (prostate cancer, breast cancer, colorectal cancer, oral cancer, and osteosarcoma) growth and survival, and can be therapeutically used against other major [...] Read more.
Capsazepine is a synthetic analogue of capsaicin that can function as an antagonist of TRPV1. Capsazepine can exhibit diverse effects on cancer (prostate cancer, breast cancer, colorectal cancer, oral cancer, and osteosarcoma) growth and survival, and can be therapeutically used against other major disorders such as colitis, pancreatitis, malaria, and epilepsy. Capsazepine has been reported to exhibit pleiotropic anti-cancer effects against numerous tumor cell lines. Capsazepine can modulate Janus activated kinase (JAK)/signal transducer and activator of the transcription (STAT) pathway, intracellular Ca2+ concentration, and reactive oxygen species (ROS)-JNK-CCAAT/enhancer-binding protein homologous protein (CHOP) pathways. It can inhibit cell proliferation, metastasis, and induce apoptosis. Moreover, capsazepine can exert anti-inflammatory effects through the downregulation of lipopolysaccharide (LPS)-induced nuclear transcription factor-kappa B (NF-κB), as well as the blockage of activation of both transient receptor potential cation channel subfamily V member 1 (TRPV1) and transient receptor potential cation channel, subfamily A, and member 1 (TRPA1). This review briefly summarizes the diverse pharmacological actions of capsazepine against various cancers and inflammatory conditions. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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20 pages, 1373 KiB  
Review
Dietary Phytochemicals Targeting Cancer Stem Cells
by Alena Liskova, Peter Kubatka, Marek Samec, Pavol Zubor, Milos Mlyncek, Tibor Bielik, Samson Mathews Samuel, Anthony Zulli, Taeg Kyu Kwon and Dietrich Büsselberg
Molecules 2019, 24(5), 899; https://doi.org/10.3390/molecules24050899 - 04 Mar 2019
Cited by 69 | Viewed by 7471
Abstract
There is an increasing awareness of the importance of a diet rich in fruits and vegetables for human health. Cancer stem cells (CSCs) are characterized as a subpopulation of cancer cells with aberrant regulation of self-renewal, proliferation or apoptosis leading to cancer progression, [...] Read more.
There is an increasing awareness of the importance of a diet rich in fruits and vegetables for human health. Cancer stem cells (CSCs) are characterized as a subpopulation of cancer cells with aberrant regulation of self-renewal, proliferation or apoptosis leading to cancer progression, invasiveness, metastasis formation, and therapy resistance. Anticancer effects of phytochemicals are also directed to target CSCs. Here we provide a comprehensive review of dietary phytochemicals targeting CSCs. Moreover, we evaluate and summarize studies dealing with effects of dietary phytochemicals on CSCs of various malignancies in preclinical and clinical research. Dietary phytochemicals have a significant impact on CSCs which may be applied in cancer prevention and treatment. However, anticancer effects of plant derived compounds have not yet been fully investigated in clinical research. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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20 pages, 415 KiB  
Review
Potential of Zerumbone as an Anti-Cancer Agent
by Sosmitha Girisa, Bano Shabnam, Javadi Monisha, Lu Fan, Clarissa Esmeralda Halim, Frank Arfuso, Kwang Seok Ahn, Gautam Sethi and Ajaikumar B. Kunnumakkara
Molecules 2019, 24(4), 734; https://doi.org/10.3390/molecules24040734 - 18 Feb 2019
Cited by 112 | Viewed by 8639
Abstract
Cancer is still a major risk factor to public health globally, causing approximately 9.8 million deaths worldwide in 2018. Despite advances in conventional treatment modalities for cancer treatment, there are still few effective therapies available due to the lack of selectivity, adverse side [...] Read more.
Cancer is still a major risk factor to public health globally, causing approximately 9.8 million deaths worldwide in 2018. Despite advances in conventional treatment modalities for cancer treatment, there are still few effective therapies available due to the lack of selectivity, adverse side effects, non-specific toxicities, and tumour recurrence. Therefore, there is an immediate need for essential alternative therapeutics, which can prove to be beneficial and safe against cancer. Various phytochemicals from natural sources have been found to exhibit beneficial medicinal properties against various human diseases. Zerumbone is one such compound isolated from Zingiber zerumbet Smith that possesses diverse pharmacological properties including those of antioxidant, antibacterial, antipyretic, anti-inflammatory, immunomodulatory, as well as anti-neoplastic. Zerumbone has shown its anti-cancer effects by causing significant suppression of proliferation, survival, angiogenesis, invasion, and metastasis through the molecular modulation of different pathways such as NF-κB, Akt, and IL-6/JAK2/STAT3 (interleukin-6/janus kinase-2/signal transducer and activator of transcription 3) and their downstream target proteins. The current review briefly summarizes the modes of action and therapeutic potential of zerumbone against various cancers. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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14 pages, 609 KiB  
Review
Biochemical Basis of Anti-Cancer-Effects of Phloretin—A Natural Dihydrochalcone
by Bu Young Choi
Molecules 2019, 24(2), 278; https://doi.org/10.3390/molecules24020278 - 13 Jan 2019
Cited by 71 | Viewed by 6080
Abstract
Apple is a rich source of bioactive phytochemicals that help improve health by preventing and/or curing many disease processes, including cancer. One of the apple polyphenols is phloretin [2′,4′,6′-Trihydroxy-3-(4-hydroxyphenyl)-propiophenone], which has been widely investigated for its antioxidant, anti-inflammatory and anti-cancer activities in a [...] Read more.
Apple is a rich source of bioactive phytochemicals that help improve health by preventing and/or curing many disease processes, including cancer. One of the apple polyphenols is phloretin [2′,4′,6′-Trihydroxy-3-(4-hydroxyphenyl)-propiophenone], which has been widely investigated for its antioxidant, anti-inflammatory and anti-cancer activities in a wide array of preclinical studies. The efficacy of phloretin in suppressing xenograft tumor growth in athymic nude mice implanted with a variety of human cancer cells, and the ability of the compound to interfere with cancer cells signaling, have made it a promising candidate for anti-cancer drug development. Mechanistically, phloretin has been reported to arrest the growth of tumor cells by blocking cyclins and cyclin-dependent kinases and induce apoptosis by activating mitochondria-mediated cell death. The blockade of the glycolytic pathway via downregulation of GLUT2 mRNA and proteins, and the inhibition of tumor cells migration, also corroborates the anti-cancer effects of phloretin. This review sheds light on the molecular targets of phloretin as a potential anti-cancer and anti-inflammatory natural agent. Full article
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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