Research

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18 pages, 11107 KiB

Open AccessArticle

[6]-Gingerol-Derived Semi-Synthetic Compound SSi6 Inhibits Tumor Growth and Metastatic Dissemination in Triple-Negative Breast Cancer Xenograft Models

by Liany Luna-Dulcey, James Almada da Silva, Veronica Jimenez-Renard, Eduardo Caleiras, Silvana Mouron, Miguel Quintela-Fandino and Marcia R. Cominetti

Cancers 2021, 13(12), 2855; https://doi.org/10.3390/cancers13122855 - 08 Jun 2021

Cited by 3 | Viewed by 2499

Abstract

Breast cancer metastasis is the most common cause of cancer death in women worldwide. Triple-negative breast cancers (TNBC) form a heterogeneous group of tumors that have higher relapse rates and poorer survival compared to other breast cancer subtypes. Thus, this work reports the [...] Read more.

Breast cancer metastasis is the most common cause of cancer death in women worldwide. Triple-negative breast cancers (TNBC) form a heterogeneous group of tumors that have higher relapse rates and poorer survival compared to other breast cancer subtypes. Thus, this work reports the antitumor and antimetastatic activities of a [6]-gingerol-derived semi-synthetic compound named SSi6 on MDA-MB-231 TNBC cells using xenograft models. SSi6 did not cause toxic effects in vivo as demonstrated by body weight and hematological and histological evaluations. From the orthotopic xenograft model, we demonstrated that SSi6 slows and inhibits the growth of the primary tumor, as well as prevents metastatic spontaneous progression from lymph nodes to the lungs. Moreover, a second xenograft model with resection of the primary tumor showed that SSi6 also blocks the progression of metastases from the lymph nodes to other visceral organs. Taken together, our results demonstrate that SSi6 is a promising compound to be investigated in other preclinical and clinical models to be applied as a complementary therapy for TNBC. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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15 pages, 1659 KiB

Open AccessArticle

Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential

by Charles S. Fermaintt, Thilini Peramuna, Shengxin Cai, Leila Takahashi-Ruiz, Jacob Nathaniel Essif, Corena V. Grant, Barry R. O’Keefe, Susan L. Mooberry, Robert H. Cichewicz and April L. Risinger

Cancers 2021, 13(11), 2834; https://doi.org/10.3390/cancers13112834 - 07 Jun 2021

Cited by 9 | Viewed by 3654

Abstract

The heterogeneity of triple negative breast cancer (TNBC) has led to efforts to further subtype this disease with the hope of identifying new molecular liabilities and drug targets. Furthermore, the finding that TNBC is the most inherently immunogenic type of breast cancer provides [...] Read more.

The heterogeneity of triple negative breast cancer (TNBC) has led to efforts to further subtype this disease with the hope of identifying new molecular liabilities and drug targets. Furthermore, the finding that TNBC is the most inherently immunogenic type of breast cancer provides the potential for effective treatment with immune checkpoint inhibitors and immune adjuvants. Thus, we devised a dual screen to identify compounds from natural product extracts with TNBC subtype selectivity that also promote the expression of cytokines associated with antitumor immunity. These efforts led to the identification of yuanhuacine (1) as a potent and highly selective inhibitor of the basal-like 2 (BL2) subtype of TNBC that also promoted an antitumor associated cytokine signature in immune cells. The mechanism of action of yuanhuacine for both phenotypes depends on activation of protein kinase C (PKC), defining a novel target for the treatment of this clinical TNBC subtype. Yuanhuacine showed potent antitumor efficacy in animals bearing BL2 tumors further demonstrating that PKC could function as a potential pharmacological target for the treatment of the BL2 subtype of TNBC. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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32 pages, 9024 KiB

Open AccessArticle

Lensoside Aβ as an Adjuvant to the Anti-Glioma Potential of Sorafenib

by Aleksandra Maciejczyk, Justyna Kapral-Piotrowska, Joanna Sumorek-Wiadro, Adrian Zając, Ewa Grela, Rafał Luchowski, Wiesław I. Gruszecki, Marta Kinga Lemieszek, Iwona Wertel, Łukasz Pecio, Jerzy Żuchowski, Krystyna Skalicka-Woźniak, Bożena Pawlikowska-Pawlęga, Monika Hułas-Stasiak, Wojciech Rzeski, Radosław Rola and Joanna Jakubowicz-Gil

Cancers 2021, 13(11), 2637; https://doi.org/10.3390/cancers13112637 - 27 May 2021

Cited by 4 | Viewed by 2871

Abstract

Aim: The anti-glioma effect of lensoside Aβ alone and in combination with sorafenib (pro-survival Raf kinase inhibitor) was evaluated for the first time in terms of programmed cell death induction in anaplastic astrocytoma and glioblastoma multiforme cell lines as an experimental model. Apoptosis, [...] Read more.

Aim: The anti-glioma effect of lensoside Aβ alone and in combination with sorafenib (pro-survival Raf kinase inhibitor) was evaluated for the first time in terms of programmed cell death induction in anaplastic astrocytoma and glioblastoma multiforme cell lines as an experimental model. Apoptosis, autophagy, and necrosis were identified microscopically (fluorescence and scanning microscopes) and confirmed by flow cytometry (mitochondrial membrane potential MMP and cell death). The expression of apoptotic (caspase 3) and autophagic markers (beclin 1) as well as Raf kinase were estimated by immunoblotting. The FTIR method was used to determine the interaction of the studied drugs with lipid and protein groups within cells, while the modes of drug action within the cells were assessed with the FLIM technique. Results: Lensoside Aβ itself does not exhibit anti-glioma activity but significantly enhances the anti-cancer potential of sorafenib, initiating mainly apoptosis of up to 90% of cells. It was correlated with an increased level of active caspase 3, a reduced MMP value, and a lower level of Raf kinase. The interaction with membrane structures led to morphological changes typical of programmed death. Conclusions: Our results indicate that lensoside Aβ plays an important role as an adjuvant in chemotherapy with sorafenib and may be a potential candidate in anti-glioma combination therapy. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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20 pages, 5876 KiB

Open AccessArticle

Rhein Suppresses Colorectal Cancer Cell Growth by Inhibiting the mTOR Pathway In Vitro and In Vivo

by Haibo Zhang, Jun-Koo Yi, Hai Huang, Song Park, Sijun Park, Wookbong Kwon, Eungyung Kim, Soyoung Jang, Si-Yong Kim, Seong-Kyoon Choi, Sung-Hyun Kim, Kangdong Liu, Zigang Dong, Zae Young Ryoo and Myoung Ok Kim

Cancers 2021, 13(9), 2176; https://doi.org/10.3390/cancers13092176 - 30 Apr 2021

Cited by 15 | Viewed by 2306

Abstract

Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. Rhein has demonstrated therapeutic effects in various cancer models. However, its effects and underlying mechanisms of action in CRC remain poorly understood. We investigated the potential anticancer [...] Read more.

Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. Rhein has demonstrated therapeutic effects in various cancer models. However, its effects and underlying mechanisms of action in CRC remain poorly understood. We investigated the potential anticancer activity and underlying mechanisms of rhein in CRC in vitro and in vivo. Cell viability and anchorage-independent colony formation assays were performed to examine the antigrowth effects of rhein on CRC cells. Wound-healing and Transwell assays were conducted to assess cell migration and invasion capacity. Cell cycle and apoptosis were investigated by flow cytometry and verified by immunoblotting. A tissue microarray was used to detect mTOR expression in CRC patient tissues. Gene overexpression and knockdown were done to analyze the function of mTOR in CRC. The anticancer effect of rhein in vivo was assessed in a CRC xenograft mouse model. The results show that rhein significantly inhibited CRC cell growth by inducing S-phase cell cycle arrest and apoptosis. Rhein inhibited CRC cell migration and invasion through the epithelial–mesenchymal transition (EMT) process. mTOR was highly expressed in CRC cancer tissues and cells. Overexpression of mTOR promoted cell growth, migration, and invasion, whereas mTOR knockdown diminished these phenomena in CRC cells in vitro. In addition, rhein directly targeted mTOR and inhibited the mTOR signaling pathway in CRC cells. Rhein promoted mTOR degradation through the ubiquitin-proteasome pathway. Intraperitoneal administration of rhein inhibited HCT116 xenograft tumor growth through the mTOR pathway. In conclusion, rhein exerts anticancer activity in vitro and in vivo by targeting mTOR and inhibiting the mTOR signaling pathway in CRC. Our results indicate that rhein is a potent anticancer agent that may be useful for the prevention and treatment of CRC. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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10 pages, 274 KiB

Open AccessArticle

Citrus Consumption and the Risk of Non-Melanoma Skin Cancer in the Women’s Health Initiative

by Junichi R. Sakaki, Melissa M. Melough, Mary B. Roberts, Charles B. Eaton, Aladdin H. Shadyab, Abrar A. Qureshi, Ock K. Chun and Eunyoung Cho

Cancers 2021, 13(9), 2173; https://doi.org/10.3390/cancers13092173 - 30 Apr 2021

Cited by 4 | Viewed by 2159

Abstract

Evidence from animal studies suggests that furocoumarins, compounds present in citrus products, can increase the risk of non-melanoma skin cancer (NMSC) when combined with ultraviolet radiation. The objective of this study was to determine the relationship between citrus intake and NMSC risk among [...] Read more.

Evidence from animal studies suggests that furocoumarins, compounds present in citrus products, can increase the risk of non-melanoma skin cancer (NMSC) when combined with ultraviolet radiation. The objective of this study was to determine the relationship between citrus intake and NMSC risk among postmenopausal women from the Women’s Health Initiative (WHI) Observational Study, who were aged 50–79 years at enrollment (1993–1998). The consumption of citrus fruit, citrus juice, and non-citrus fruit and juice were measured at the baseline of the study using a food frequency questionnaire (FFQ). NMSC cases (basal or squamous cell carcinomas) were self-reported during annual follow-up surveys. The outcome data used for this analysis were collected through March 2020. The relative risk (RR) for incident NMSC by citrus consumption was calculated. Among 49,007 non-Hispanic white participants, there were 8642 cases of incident NMSC. Using less than one serving of citrus juice per week as reference, the RRs and 95% confidence intervals (CI) for incident NMSC by citrus juice intake were 1.03 (0.95, 1.10) for one serving/week, 1.06 (1.00, 1.12) for two to four servings/week, 0.98 (0.90, 1.07) for five to six servings/week, and 1.08 (1.02, 1.13) for one or more serving/day (p-trend = 0.007). Subgroup analyses did not reveal meaningful associations by sun exposure variables. In conclusion, there were indications of a slightly higher risk of incident NMSC among citrus juice consumers; however, further longitudinal and mechanistic studies are needed to confirm the key risk factors. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

14 pages, 1965 KiB

Open AccessArticle

Palmitoylethanolamide Reduces Colon Cancer Cell Proliferation and Migration, Influences Tumor Cell Cycle and Exerts In Vivo Chemopreventive Effects

by Ester Pagano, Tommaso Venneri, Giuseppe Lucariello, Donatella Cicia, Vincenzo Brancaleone, M. Francesca Nanì, Nunzio A. Cacciola, Raffaele Capasso, Angelo A. Izzo, Francesca Borrelli and Barbara Romano

Cancers 2021, 13(8), 1923; https://doi.org/10.3390/cancers13081923 - 16 Apr 2021

Cited by 20 | Viewed by 4006

Abstract

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the endocannabinoid anandamide. PEA exerts intestinal anti-inflammatory effects, but knowledge of its role in colon carcinogenesis is still largely fragmentary. We deepened this aspect by studying the effects of PEA (ultramicronized PEA, um-PEA) [...] Read more.

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the endocannabinoid anandamide. PEA exerts intestinal anti-inflammatory effects, but knowledge of its role in colon carcinogenesis is still largely fragmentary. We deepened this aspect by studying the effects of PEA (ultramicronized PEA, um-PEA) on colon cancer cell proliferation, migration and cell cycle as well as its effects in a murine model of colon cancer. Results showed that um-PEA inhibited tumor cell proliferation via peroxisome proliferator-activated receptor α and G protein-coupled receptor 55, induced cell cycle arrest in the G2/M phase, possibly through cyclin B1/CDK1 upregulation, and induced DNA fragmentation. Furthermore, um-PEA reduced tumor cell migration by reducing MMP2 and TIMP1 expression. In vivo administration of um-PEA exerted beneficial effects in the azoxymethane model of colonic tumors, by reducing the number of preneoplastic lesions and tumors. Collectively, our findings provide novel proofs on the effects of um-PEA in colon carcinogenesis. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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18 pages, 2628 KiB

Open AccessArticle

Permeability of Hypogymnia physodes Extract Component—Physodic Acid through the Blood–Brain Barrier as an Important Argument for Its Anticancer and Neuroprotective Activity within the Central Nervous System

by Elżbieta Studzińska-Sroka, Aleksandra Majchrzak-Celińska, Przemysław Zalewski, Dominik Szwajgier, Ewa Baranowska-Wójcik, Marcin Żarowski, Tomasz Plech and Judyta Cielecka-Piontek

Cancers 2021, 13(7), 1717; https://doi.org/10.3390/cancers13071717 - 05 Apr 2021

Cited by 16 | Viewed by 3056

Abstract

Lichen secondary metabolites are characterized by huge pharmacological potential. Our research focused on assessing the anticancer and neuroprotective activity of Hypogymnia physodes acetone extract (HP extract) and physodic acid, its major component. The antitumor properties were evaluated by cytotoxicity analysis using A-172, T98G, [...] Read more.

Lichen secondary metabolites are characterized by huge pharmacological potential. Our research focused on assessing the anticancer and neuroprotective activity of Hypogymnia physodes acetone extract (HP extract) and physodic acid, its major component. The antitumor properties were evaluated by cytotoxicity analysis using A-172, T98G, and U-138 MG glioblastoma cell lines and by hyaluronidase and cyclooxygenase-2 (COX-2) inhibition. The neuroprotective potential was examined using COX-2, tyrosinase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) activity tests. Moreover, the antioxidant potential of the tested substances was examined, and the chemical composition of the extract was analyzed. For physodic acid, the permeability through the blood–brain barrier using Parallel Artificial Membrane Permeability Assay for the Blood–Brain Barrier assay (PAMPA-BBB) was assessed. Our study shows that the tested substances strongly inhibited glioblastoma cell proliferation and hyaluronidase activity. Besides, HP extract diminished COX-2 and tyrosinase activity. However, the AChE and BChE inhibitory activity of HP extract and physodic acid were mild. The examined substances exhibited strong antioxidant activity. Importantly, we proved that physodic acid crosses the blood–brain barrier. We conclude that physodic acid and H. physodes should be regarded as promising agents with anticancer, chemopreventive, and neuroprotective activities, especially regarding the central nervous system diseases. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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15 pages, 3281 KiB

Open AccessArticle

Momordicine-I, a Bitter Melon Bioactive Metabolite, Displays Anti-Tumor Activity in Head and Neck Cancer Involving c-Met and Downstream Signaling

by Subhayan Sur, Robert Steele, T. Scott Isbell, Kalyan Nagulapalli Venkata, Mostafa E. Rateb and Ratna B. Ray

Cancers 2021, 13(6), 1432; https://doi.org/10.3390/cancers13061432 - 21 Mar 2021

Cited by 7 | Viewed by 2653

Abstract

Head and neck cancer (HNC) is one of the most aggressive cancers, and treatments are quite challenging due to the difficulty in early diagnosis, lack of effective chemotherapeutic drugs, adverse side effects and therapy resistance. We identified momordicine-I (M-I), a bioactive secondary metabolite [...] Read more.

Head and neck cancer (HNC) is one of the most aggressive cancers, and treatments are quite challenging due to the difficulty in early diagnosis, lack of effective chemotherapeutic drugs, adverse side effects and therapy resistance. We identified momordicine-I (M-I), a bioactive secondary metabolite in bitter melon (Momordica charantia), by performing liquid chromatography-high resolution electrospray ionization mass spectrometry (LC-HRESIMS) analysis. M-I inhibited human HNC cell (JHU022, JHU029, Cal27) viability in a dose-dependent manner without an apparent toxic effect on normal oral keratinocytes. Mechanistic studies showed that M-I inhibited c-Met and its downstream signaling molecules c-Myc, survivin, and cyclin D1 through the inactivation of STAT3 in HNC cells. We further observed that M-I was non-toxic and stable in mouse (male C57Bl/6) blood, and a favorable pharmacokinetics profile was observed after IP administration. M-I treatment reduced HNC xenograft tumor growth in nude mice and inhibited c-Met and downstream signaling. Thus, M-I has potential therapeutic implications against HNC. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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20 pages, 34849 KiB

Open AccessArticle

Isoliquiritigenin Reverses Epithelial-Mesenchymal Transition Through Modulation of the TGF-β/Smad Signaling Pathway in Endometrial Cancer

by Hsin-Yuan Chen, Yi-Fen Chiang, Jia-Syuan Huang, Tsui-Chin Huang, Yin-Hwa Shih, Kai-Lee Wang, Mohamed Ali, Yong-Han Hong, Tzong-Ming Shieh and Shih-Min Hsia

Cancers 2021, 13(6), 1236; https://doi.org/10.3390/cancers13061236 - 11 Mar 2021

Cited by 24 | Viewed by 3134

Abstract

Endometrial cancer is a common gynecological cancer with a poor prognosis, mostly attributed to tumor metastasis. Epithelial–mesenchymal transition (EMT) can be mediated via transforming growth factor beta (TGF-β) signaling pathway, facilitating the ability of cancer cell invasion and migration. Isoliquiritigenin (ISL) is a [...] Read more.

Endometrial cancer is a common gynecological cancer with a poor prognosis, mostly attributed to tumor metastasis. Epithelial–mesenchymal transition (EMT) can be mediated via transforming growth factor beta (TGF-β) signaling pathway, facilitating the ability of cancer cell invasion and migration. Isoliquiritigenin (ISL) is a flavonoid derived from licorice with reported antineoplastic activities. This study aims to investigate the anti-metastatic potential of ISL on endometrial cancer both in vitro and in vivo. First, human endometrial cancer cell lines (HEC-1A, Ishikawa, and RL95-2) were treated with ISL and then subjected to functional assays such as migration assay as well as molecular analyses including immunoblotting, immunofluorescence and RT-qPCR. In addition, HEC-1A-LUC cells were implanted into female nude mice and treated with ISL by intraperitoneal injection for four weeks. Results showed that ISL inhibited cell migration and reversed the effect of TGF-β on the expression of E-cadherin, N-cadherin, vimentin, α-SMA, p-Smad3, and TWIST1/2 In vitro. Interestingly, In vivo study revealed that ISL reduced peritoneal dissemination and serum level of TGF-β1, as well as decreased the expression levels of N-cadherin, p-Smad2/3, TWIST1/2, while increased E-cadherin. Overall, ISL reverses the EMT through targeting the TGF-β/Smad signaling pathway and features a potential therapeutic treatment for metastatic endometrial cancer. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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21 pages, 4213 KiB

Open AccessArticle

Novel Caffeic Acid Phenethyl Ester-Mortalin Antibody Nanoparticles Offer Enhanced Selective Cytotoxicity to Cancer Cells

by Jia Wang, Priyanshu Bhargava, Yue Yu, Anissa Nofita Sari, Huayue Zhang, Noriyuki Ishii, Kangmin Yan, Zhenya Zhang, Yoshiyuki Ishida, Keiji Terao, Sunil C. Kaul, Eijiro Miyako and Renu Wadhwa

Cancers 2020, 12(9), 2370; https://doi.org/10.3390/cancers12092370 - 21 Aug 2020

Cited by 21 | Viewed by 3868

Abstract

Caffeic acid phenethyl ester (CAPE) is a key bioactive ingredient of honeybee propolis and is claimed to have anticancer activity. Since mortalin, a hsp70 chaperone, is enriched in a cancerous cell surface, we recruited a unique cell internalizing anti-mortalin antibody (MotAb) to generate [...] Read more.

Caffeic acid phenethyl ester (CAPE) is a key bioactive ingredient of honeybee propolis and is claimed to have anticancer activity. Since mortalin, a hsp70 chaperone, is enriched in a cancerous cell surface, we recruited a unique cell internalizing anti-mortalin antibody (MotAb) to generate mortalin-targeting CAPE nanoparticles (CAPE-MotAb). Biophysical and biomolecular analyses revealed enhanced anticancer activity of CAPE-MotAb both in in vitro and in vivo assays. We demonstrate that CAPE-MotAb cause a stronger dose-dependent growth arrest/apoptosis of cancer cells through the downregulation of Cyclin D1-CDK4, phospho-Rb, PARP-1, and anti-apoptotic protein Bcl2. Concomitantly, a significant increase in the expression of p53, p21^WAF1, and caspase cleavage was obtained only in CAPE-MotAb treated cells. We also demonstrate that CAPE-MotAb caused a remarkably enhanced downregulation of proteins critically involved in cell migration. In vivo tumor growth assays for subcutaneous xenografts in nude mice also revealed a significantly enhanced suppression of tumor growth in the treated group suggesting that these novel CAPE-MotAb nanoparticles may serve as a potent anticancer nanomedicine. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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17 pages, 2334 KiB

Open AccessArticle

The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells

by Pei-Ching Hsiao, Jer-Hwa Chang, Wei-Jiunn Lee, Chia-Chi Ku, Meng-Ying Tsai, Shun-Fa Yang and Ming-Hsien Chien

Cancers 2020, 12(8), 2163; https://doi.org/10.3390/cancers12082163 - 04 Aug 2020

Cited by 18 | Viewed by 2658

Abstract

Curcumin (CUR) has a range of therapeutic benefits against cancers, but its poor solubility and low bioavailability limit its clinical use. Demethoxycurcumin (DMC) and diphenyl difluoroketone (EF-24) are natural and synthetic curcumin analogues, respectively, with better solubilities and higher anti-carcinogenic activities in various [...] Read more.

Curcumin (CUR) has a range of therapeutic benefits against cancers, but its poor solubility and low bioavailability limit its clinical use. Demethoxycurcumin (DMC) and diphenyl difluoroketone (EF-24) are natural and synthetic curcumin analogues, respectively, with better solubilities and higher anti-carcinogenic activities in various solid tumors than CUR. However, the efficacy of these analogues against non-solid tumors, particularly in acute myeloid leukemia (AML), has not been fully investigated. Herein, we observed that both DMC and EF-24 significantly decrease the proportion of viable AML cells including HL-60, U937, and MV4-11, harboring different NRAS and Fms-like tyrosine kinase 3 (FLT3) statuses, and that EF-24 has a lower half maximal inhibitory concentration (IC₅₀) than DMC. We found that EF-24 treatment induces several features of apoptosis, including an increase in the sub-G₁ population, phosphatidylserine (PS) externalization, and significant activation of extrinsic proapoptotic signaling such as caspase-8 and -3 activation. Mechanistically, p38 mitogen-activated protein kinase (MAPK) activation is critical for EF-24-triggered apoptosis via activating protein phosphatase 2A (PP2A) to attenuate extracellular-regulated protein kinase (ERK) activities in HL-60 AML cells. In the clinic, patients with AML expressing high level of PP2A have the most favorable prognoses compared to various solid tumors. Taken together, our results indicate that EF-24 is a potential therapeutic agent for treating AML, especially for cancer types that lose the function of the PP2A tumor suppressor. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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Review

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57 pages, 53096 KiB

Open AccessReview

Do Lipid-based Nanoparticles Hold Promise for Advancing the Clinical Translation of Anticancer Alkaloids?

by Jian Sheng Loh, Li Kar Stella Tan, Wai Leng Lee, Long Chiau Ming, Chee Wun How, Jhi Biau Foo, Nurolaini Kifli, Bey Hing Goh and Yong Sze Ong

Cancers 2021, 13(21), 5346; https://doi.org/10.3390/cancers13215346 - 25 Oct 2021

Cited by 12 | Viewed by 3753

Abstract

Since the commercialization of morphine in 1826, numerous alkaloids have been isolated and exploited effectively for the betterment of mankind, including cancer treatment. However, the commercialization of alkaloids as anticancer agents has generally been limited by serious side effects due to their lack [...] Read more.

Since the commercialization of morphine in 1826, numerous alkaloids have been isolated and exploited effectively for the betterment of mankind, including cancer treatment. However, the commercialization of alkaloids as anticancer agents has generally been limited by serious side effects due to their lack of specificity to cancer cells, indiscriminate tissue distribution and toxic formulation excipients. Lipid-based nanoparticles represent the most effective drug delivery system concerning clinical translation owing to their unique, appealing characteristics for drug delivery. To the extent of our knowledge, this is the first review to compile in vitro and in vivo evidence of encapsulating anticancer alkaloids in lipid-based nanoparticles. Alkaloids encapsulated in lipid-based nanoparticles have generally displayed enhanced in vitro cytotoxicity and an improved in vivo efficacy and toxicity profile than free alkaloids in various cancers. Encapsulated alkaloids also demonstrated the ability to overcome multidrug resistance in vitro and in vivo. These findings support the broad application of lipid-based nanoparticles to encapsulate anticancer alkaloids and facilitate their clinical translation. The review then discusses several limitations of the studies analyzed, particularly the discrepancies in reporting the pharmacokinetics, biodistribution and toxicity data. Finally, we conclude with examples of clinically successful encapsulated alkaloids that have received regulatory approval and are undergoing clinical evaluation. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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21 pages, 3205 KiB

Open AccessReview

Anticancer Mechanisms of Bioactive Compounds from Solanaceae: An Update

by David O. Nkwe, Bonolo Lotshwao, Gaolathe Rantong, James Matshwele, Tebogo E. Kwape, Kabo Masisi, Goabaone Gaobotse, Kathleen Hefferon and Abdullah Makhzoum

Cancers 2021, 13(19), 4989; https://doi.org/10.3390/cancers13194989 - 05 Oct 2021

Cited by 11 | Viewed by 3026

Abstract

Plants continue to provide unlimited pharmacologically active compounds that can treat various illnesses, including cancer. The Solanaceae family, besides providing economically important food plants, such as potatoes and tomatoes, has been exploited extensively in folk medicine, as it provides an array of bioactive [...] Read more.

Plants continue to provide unlimited pharmacologically active compounds that can treat various illnesses, including cancer. The Solanaceae family, besides providing economically important food plants, such as potatoes and tomatoes, has been exploited extensively in folk medicine, as it provides an array of bioactive compounds. Many studies have demonstrated the anticancer potency of some of the compounds, but the corresponding molecular targets are not well defined. However, advances in molecular cell biology and in silico modelling have made it possible to dissect some of the underlying mechanisms. By reviewing the literature over the last five years, we provide an update on anticancer mechanisms associated with phytochemicals isolated from species in the Solanaceae plant family. These mechanisms are conveniently grouped into cell cycle arrest, transcription regulation, modulation of autophagy, inhibition of signalling pathways, suppression of metabolic enzymes, and membrane disruption. The majority of the bioactive compounds exert their antiproliferative effects by inhibiting diverse signalling pathways, as well as arresting the cell cycle. Furthermore, some of the phytochemicals are effective against more than one cancer type. Therefore, understanding these mechanisms provides paths for future formulation of novel anticancer drugs, as well as highlighting potential areas of research. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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30 pages, 2805 KiB

Open AccessReview

Current Perspective on the Natural Compounds and Drug Delivery Techniques in Glioblastoma Multiforme

by Tapan Behl, Aditi Sharma, Lalit Sharma, Aayush Sehgal, Sukhbir Singh, Neelam Sharma, Gokhan Zengin, Simona Bungau, Mirela Marioara Toma, Daniela Gitea, Elena Emilia Babes, Claudia Teodora Judea Pusta and Adrian Gheorghe Bumbu

Cancers 2021, 13(11), 2765; https://doi.org/10.3390/cancers13112765 - 02 Jun 2021

Cited by 17 | Viewed by 4389

Abstract

Glioblastoma multiforme (GBM) is one of the debilitating brain tumors, being associated with extremely poor prognosis and short median patient survival. GBM is associated with complex pathogenesis with alterations in various cellular signaling events, that participate in cell proliferation and survival. The impairment [...] Read more.

Glioblastoma multiforme (GBM) is one of the debilitating brain tumors, being associated with extremely poor prognosis and short median patient survival. GBM is associated with complex pathogenesis with alterations in various cellular signaling events, that participate in cell proliferation and survival. The impairment in cellular redox pathways leads to tumorigenesis. The current standard pharmacological regimen available for glioblastomas, such as radiotherapy and surgical resection following treatment with chemotherapeutic drug temozolomide, remains fatal, due to drug resistance, metastasis and tumor recurrence. Thus, the demand for an effective therapeutic strategy for GBM remains elusive. Hopefully, novel products from natural compounds are suggested as possible solutions. They protect glial cells by reducing oxidative stress and neuroinflammation, inhibiting proliferation, inducing apoptosis, inhibiting pro-oncogene events and intensifying the potent anti-tumor therapies. Targeting aberrant cellular pathways in the amelioration of GBM could promote the development of new therapeutic options that improve patient quality of life and extend survival. Consequently, our review emphasizes several natural compounds in GBM treatment. We also assessed the potential of drug delivery techniques such as nanoparticles, Gliadel wafers and drug delivery using cellular carriers which could lead to a novel path for the obliteration of GBM. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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52 pages, 3829 KiB

Open AccessReview

Is Emodin with Anticancer Effects Completely Innocent? Two Sides of the Coin

by Esra Küpeli Akkol, Iffet Irem Tatlı, Gökçe Şeker Karatoprak, Osman Tuncay Ağar, Çiğdem Yücel, Eduardo Sobarzo-Sánchez and Raffaele Capasso

Cancers 2021, 13(11), 2733; https://doi.org/10.3390/cancers13112733 - 31 May 2021

Cited by 71 | Viewed by 6859

Abstract

Many anticancer active compounds are known to have the capacity to destroy pathologically proliferating cancer cells in the body, as well as to destroy rapidly proliferating normal cells. Despite remarkable advances in cancer research over the past few decades, the inclusion of natural [...] Read more.

Many anticancer active compounds are known to have the capacity to destroy pathologically proliferating cancer cells in the body, as well as to destroy rapidly proliferating normal cells. Despite remarkable advances in cancer research over the past few decades, the inclusion of natural compounds in researches as potential drug candidates is becoming increasingly important. However, the perception that the natural is reliable is an issue that needs to be clarified. Among the various chemical classes of natural products, anthraquinones have many biological activities and have also been proven to exhibit a unique anticancer activity. Emodin, an anthraquinone derivative, is a natural compound found in the roots and rhizomes of many plants. The anticancer property of emodin, a broad-spectrum inhibitory agent of cancer cells, has been detailed in many biological pathways. In cancer cells, these molecular mechanisms consist of suppressing cell growth and proliferation through the attenuation of oncogenic growth signaling, such as protein kinase B (AKT), mitogen-activated protein kinase (MAPK), HER-2 tyrosine kinase, Wnt/-catenin, and phosphatidylinositol 3-kinase (PI3K). However, it is known that emodin, which shows toxicity to cancer cells, may cause kidney toxicity, hepatotoxicity, and reproductive toxicity especially at high doses and long-term use. At the same time, studies of emodin, which has poor oral bioavailability, to transform this disadvantage into an advantage with nano-carrier systems reveal that natural compounds are not always directly usable compounds. Consequently, this review aimed to shed light on the anti-proliferative and anti-carcinogenic properties of emodin, as well as its potential toxicities and the advantages of drug delivery systems on bioavailability. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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34 pages, 12482 KiB

Open AccessReview

Molecular Mechanisms of Antiproliferative Effects of Natural Chalcones

by Radka Michalkova, Ladislav Mirossay, Maria Gazdova, Martin Kello and Jan Mojzis

Cancers 2021, 13(11), 2730; https://doi.org/10.3390/cancers13112730 - 31 May 2021

Cited by 35 | Viewed by 4168

Abstract

Although great progress has been made in the treatment of cancer, the search for new promising molecules with antitumor activity is still one of the greatest challenges in the fight against cancer due to the increasing number of new cases each year. Chalcones [...] Read more.

Although great progress has been made in the treatment of cancer, the search for new promising molecules with antitumor activity is still one of the greatest challenges in the fight against cancer due to the increasing number of new cases each year. Chalcones (1,3-diphenyl-2-propen-1-one), the precursors of flavonoid synthesis in higher plants, possess a wide spectrum of biological activities including antimicrobial, anti-inflammatory, antioxidant, and anticancer. A plethora of molecular mechanisms of action have been documented, including induction of apoptosis, autophagy, or other types of cell death, cell cycle changes, and modulation of several signaling pathways associated with cell survival or death. In addition, blockade of several steps of angiogenesis and proteasome inhibition has also been documented. This review summarizes the basic molecular mechanisms related to the antiproliferative effects of chalcones, focusing on research articles from the years January 2015–February 2021. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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43 pages, 2605 KiB

Open AccessReview

Multiple Myeloma Inhibitory Activity of Plant Natural Products

by Karin Jöhrer and Serhat Sezai Ҫiҫek

Cancers 2021, 13(11), 2678; https://doi.org/10.3390/cancers13112678 - 29 May 2021

Cited by 15 | Viewed by 6386

Abstract

A literature search on plant natural products with antimyeloma activity until the end of 2020 resulted in 92 compounds with effects on at least one human myeloma cell line. Compounds were divided in different compound classes and both their structure–activity-relationships as well as [...] Read more.

A literature search on plant natural products with antimyeloma activity until the end of 2020 resulted in 92 compounds with effects on at least one human myeloma cell line. Compounds were divided in different compound classes and both their structure–activity-relationships as well as eventual correlations with the pathways described for Multiple Myeloma were discussed. Each of the major compound classes in this review (alkaloids, phenolics, terpenes) revealed interesting candidates, such as dioncophyllines, a group of naphtylisoquinoline alkaloids, which showed pronounced and selective induction of apoptosis when substituted in position 7 of the isoquinoline moiety. Interestingly, out of the phenolic compound class, two of the most noteworthy constituents belong to the relatively small subclass of xanthones, rendering this group a good starting point for possible further drug development. The class of terpenoids also provides noteworthy constituents, such as the highly oxygenated diterpenoid oridonin, which exhibited antiproliferative effects equal to those of bortezomib on RPMI8226 cells. Moreover, triterpenoids containing a lactone ring and/or quinone-like substructures, e.g., bruceantin, whitaferin A, withanolide F, celastrol, and pristimerin, displayed remarkable activity, with the latter two compounds acting as inhibitors of both NF-κB and proteasome chymotrypsin-like activity. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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36 pages, 17147 KiB

Open AccessReview

Natural Compounds in Glioblastoma Therapy: Preclinical Insights, Mechanistic Pathways, and Outlook

by Kevin Zhai, Manaal Siddiqui, Basma Abdellatif, Alena Liskova, Peter Kubatka and Dietrich Büsselberg

Cancers 2021, 13(10), 2317; https://doi.org/10.3390/cancers13102317 - 12 May 2021

Cited by 24 | Viewed by 5900

Abstract

Glioblastoma (GBM) is an aggressive, often fatal astrocyte-derived tumor of the central nervous system. Conventional medical and surgical interventions have greatly improved survival rates; however, tumor heterogeneity, invasiveness, and chemotherapeutic resistance continue to pose clinical challenges. As such, dietary natural substances—an integral component [...] Read more.

Glioblastoma (GBM) is an aggressive, often fatal astrocyte-derived tumor of the central nervous system. Conventional medical and surgical interventions have greatly improved survival rates; however, tumor heterogeneity, invasiveness, and chemotherapeutic resistance continue to pose clinical challenges. As such, dietary natural substances—an integral component of the lifestyle medicine approach to chronic diseases—are examined as potential chemotherapeutic agents. These heterogenous substances exert anti-GBM effects by upregulating apoptosis and autophagy, inducing cell cycle arrest, interfering with tumor metabolism, and inhibiting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis. Although these beneficial effects are promising, natural substances’ efficacy in GBM is constrained by their bioavailability and blood–brain barrier permeability; various chemical formulations are proposed to improve their pharmacological properties. Many of the reviewed substances are available as over-the-counter dietary supplements, underscoring their viability as lifestyle interventions. However, clinical trials remain necessary to substantiate the in vitro and in vivo properties of natural substances. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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36 pages, 10527 KiB

Open AccessReview

Flavonoids Alleviate Peripheral Neuropathy Induced by Anticancer Drugs

by Manaal Siddiqui, Basma Abdellatif, Kevin Zhai, Alena Liskova, Peter Kubatka and Dietrich Büsselberg

Cancers 2021, 13(7), 1576; https://doi.org/10.3390/cancers13071576 - 29 Mar 2021

Cited by 14 | Viewed by 4534

Abstract

Purpose: This study aimed to assess the potential of flavonoids in combating CIPN. Methods: PubMed and Google Scholar were used, and studies that investigated flavonoids in models of CIPN and models of neuropathic pain similar to CIPN were included. Only studies investigating peripheral [...] Read more.

Purpose: This study aimed to assess the potential of flavonoids in combating CIPN. Methods: PubMed and Google Scholar were used, and studies that investigated flavonoids in models of CIPN and models of neuropathic pain similar to CIPN were included. Only studies investigating peripheral mechanisms of CIPN were used. Results: Flavonoids inhibit several essential mechanisms of CIPN, such as proinflammatory cytokine release, astrocyte and microglial activation, oxidative stress, neuronal damage and apoptosis, mitochondrial damage, ectopic discharge, and ion channel activation. They decreased the severity of certain CIPN symptoms, such as thermal hyperalgesia and mechanical, tactile, and cold allodynia. Conclusions: Flavonoids hold immense promise in treating CIPN; thus, future research should investigate their effects in humans. Specifically, precise pharmacological mechanisms and side effects need to be elucidated in human models before clinical benefits can be achieved. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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33 pages, 3530 KiB

Open AccessReview

Precision Nutrition to Activate Thermogenesis as a Complementary Approach to Target Obesity and Associated-Metabolic-Disorders

by Marina Reguero, Marta Gómez de Cedrón, Sonia Wagner, Guillermo Reglero, José Carlos Quintela and Ana Ramírez de Molina

Cancers 2021, 13(4), 866; https://doi.org/10.3390/cancers13040866 - 18 Feb 2021

Cited by 13 | Viewed by 7366

Abstract

Obesity is associated to increased incidence and poorer prognosis in multiple cancers, contributing to up to 20% of cancer related deaths. These associations are mainly driven by metabolic and inflammatory changes in the adipose tissue during obesity, which disrupt the physiologic metabolic homeostasis. [...] Read more.

Obesity is associated to increased incidence and poorer prognosis in multiple cancers, contributing to up to 20% of cancer related deaths. These associations are mainly driven by metabolic and inflammatory changes in the adipose tissue during obesity, which disrupt the physiologic metabolic homeostasis. The association between obesity and hypercholesterolemia, hypertension, cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) is well known. Importantly, the retrospective analysis of more than 1000 epidemiological studies have also shown the positive correlation between the excess of fatness with the risk of cancer. In addition, more important than weight, it is the dysfunctional adipose tissue the main driver of insulin resistance, metabolic syndrome and all cause of mortality and cancer deaths, which also explains why normal weight individuals may behave as “metabolically unhealthy obese” individuals. Adipocytes also have direct effects on tumor cells through paracrine signaling. Downregulation of adiponectin and upregulation of leptin in serum correlate with markers of chronic inflammation, and crown like structures (CLS) associated to the adipose tissue disfunction. Nevertheless, obesity is a preventable risk factor in cancer. Lifestyle interventions might contribute to reduce the adverse effects of obesity. Thus, Mediterranean diet interventional studies have been shown to reduce to circulation inflammatory factors, insulin sensitivity and cardiovascular function, with durable responses of up to 2 years in obese patients. Mediterranean diet supplemented with extra-virgin olive oil reduced the incidence of breast cancer compared with a control diet. Physical activity is another important lifestyle factor which may also contribute to reduced systemic biomarkers of metabolic syndrome associated to obesity. In this scenario, precision nutrition may provide complementary approaches to target the metabolic inflammation associated to “unhealthy obesity”. Herein, we first describe the different types of adipose tissue -thermogenic active brown adipose tissue (BAT) versus the energy storing white adipose tissue (WAT). We then move on precision nutrition based strategies, by mean of natural extracts derived from plants and/or diet derived ingredients, which may be useful to normalize the metabolic inflammation associated to “unhealthy obesity”. More specifically, we focus on two axis: (1) the activation of thermogenesis in BAT and browning of WAT; (2) and the potential of augmenting the oxidative capacity of muscles to dissipate energy. These strategies may be particularly relevant as complementary approaches to alleviate obesity associated effects on chronic inflammation, immunosuppression, angiogenesis and chemotherapy resistance in cancer. Finally, we summarize main studies where plant derived extracts, mainly, polyphenols and flavonoids, have been applied to increase the energy expenditure. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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48 pages, 4245 KiB

Open AccessReview

Chemopreventive Potential of Caryophyllane Sesquiterpenes: An Overview of Preliminary Evidence

by Antonella Di Sotto, Romina Mancinelli, Marco Gullì, Margherita Eufemi, Caterina Loredana Mammola, Gabriela Mazzanti and Silvia Di Giacomo

Cancers 2020, 12(10), 3034; https://doi.org/10.3390/cancers12103034 - 18 Oct 2020

Cited by 41 | Viewed by 4824

Abstract

Chemoprevention is referred to as a strategy to inhibit, suppress, or reverse tumor development and progression in healthy people along with high-risk subjects and oncologic patients through using pharmacological or natural substances. Numerous phytochemicals have been widely described in the literature to possess [...] Read more.

Chemoprevention is referred to as a strategy to inhibit, suppress, or reverse tumor development and progression in healthy people along with high-risk subjects and oncologic patients through using pharmacological or natural substances. Numerous phytochemicals have been widely described in the literature to possess chemopreventive properties, although their clinical usefulness remains to be defined. Among them, caryophyllane sesquiterpenes are natural compounds widely occurring in nature kingdoms, especially in plants, fungi, and marine environments. Several structures, characterized by a common caryophyllane skeleton with further rearrangements, have been identified, but those isolated from plant essential oils, including β-caryophyllene, β-caryophyllene oxide, α-humulene, and isocaryophyllene, have attracted the greatest pharmacological attention. Emerging evidence has outlined a complex polypharmacological profile of caryophyllane sesquiterpenes characterized by blocking, suppressing, chemosensitizing, and cytoprotective properties, which suggests a possible usefulness of these natural substances in cancer chemoprevention for both preventive and adjuvant purposes. In the present review, the scientific knowledge about the chemopreventive properties of caryophyllane sesquiterpenes and the mechanisms involved have been collected and discussed; moreover, possible structure–activity relationships have been highlighted. Although further high-quality studies are required, the promising preclinical findings and the safe pharmacological profile encourage further studies to define a clinical usefulness of caryophyllane sesquiterpenes in primary, secondary, or tertiary chemoprevention. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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47 pages, 7278 KiB

Open AccessReview

An In Vitro Evaluation of the Molecular Mechanisms of Action of Medical Plants from the Lamiaceae Family as Effective Sources of Active Compounds against Human Cancer Cell Lines

by Przemysław Sitarek, Anna Merecz-Sadowska, Tomasz Śliwiński, Radosław Zajdel and Tomasz Kowalczyk

Cancers 2020, 12(10), 2957; https://doi.org/10.3390/cancers12102957 - 13 Oct 2020

Cited by 22 | Viewed by 5297

Abstract

It is predicted that 1.8 million new cancer cases will be diagnosed worldwide in 2020; of these, the incidence of lung, colon, breast, and prostate cancers will be 22%, 9%, 7%, and 5%, respectively according to the National Cancer Institute. As the global [...] Read more.

It is predicted that 1.8 million new cancer cases will be diagnosed worldwide in 2020; of these, the incidence of lung, colon, breast, and prostate cancers will be 22%, 9%, 7%, and 5%, respectively according to the National Cancer Institute. As the global medical cost of cancer in 2020 will exceed about $150 billion, new approaches and novel alternative chemoprevention molecules are needed. Research indicates that the plants of the Lamiaceae family may offer such potential. The present study reviews selected species from the Lamiaceae and their active compounds that may have the potential to inhibit the growth of lung, breast, prostate, and colon cancer cells; it examines the effects of whole extracts, individual compounds, and essential oils, and it discusses their underlying molecular mechanisms of action. The studied members of the Lamiaceae are sources of crucial phytochemicals that may be important modulators of cancer-related molecular targets and can be used as effective factors to support anti-tumor treatment. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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41 pages, 1909 KiB

Open AccessReview

Carotenoids in Cancer Apoptosis—The Road from Bench to Bedside and Back

by Lenka Koklesova, Alena Liskova, Marek Samec, Constanze Buhrmann, Samson Mathews Samuel, Elizabeth Varghese, Milad Ashrafizadeh, Masoud Najafi, Mehdi Shakibaei, Dietrich Büsselberg, Frank A. Giordano, Olga Golubnitschaja and Peter Kubatka

Cancers 2020, 12(9), 2425; https://doi.org/10.3390/cancers12092425 - 26 Aug 2020

Cited by 62 | Viewed by 8976

Abstract

An incidence and mortality of cancer are rapidly growing worldwide, especially due to heterogeneous character of the disease that is associated with irreversible impairment of cellular homeostasis and function. Targeting apoptosis, one of cancer hallmarks, represents a potent cancer treatment strategy. Carotenoids are [...] Read more.

An incidence and mortality of cancer are rapidly growing worldwide, especially due to heterogeneous character of the disease that is associated with irreversible impairment of cellular homeostasis and function. Targeting apoptosis, one of cancer hallmarks, represents a potent cancer treatment strategy. Carotenoids are phytochemicals represented by carotenes, xanthophylls, and derived compounds such as apocarotenoids that demonstrate a broad spectrum of anti-cancer effects involving pro-apoptotic signaling through extrinsic and intrinsic pathways. As demonstrated in preclinical oncology research, the apoptotic modulation is performed at post-genomic levels. Further, carotenoids demonstrate additive/synergistic action in combination with conventional oncostatic agents. In addition, a sensitization of tumor cells to anti-cancer conventional treatment can be achieved by carotenoids. The disadvantage of anti-cancer application of carotenoids is associated with their low solubility and, therefore, poor bioavailability. However, this deficiency can be improved by using nanotechnological approaches, solid dispersions, microemulsions or biofortification that significantly increase the anti-cancer and pro-apoptotic efficacy of carotenoids. Only limited number of studies dealing with apoptotic potential of carotenoids has been published in clinical sphere. Pro-apoptotic effects of carotenoids should be beneficial for individuals at high risk of cancer development. The article considers the utility of carotenoids in the framework of 3P medicine. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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34 pages, 2468 KiB

Open AccessReview

Targeting Multiple Signaling Pathways in Cancer: The Rutin Therapeutic Approach

by Zeinab Nouri, Sajad Fakhri, Keyvan Nouri, Carly E. Wallace, Mohammad Hosein Farzaei and Anupam Bishayee

Cancers 2020, 12(8), 2276; https://doi.org/10.3390/cancers12082276 - 14 Aug 2020

Cited by 102 | Viewed by 8083

Abstract

Multiple dysregulated signaling pathways are implicated in the pathogenesis of cancer. The conventional therapies used in cancer prevention/treatment suffer from low efficacy, considerable toxicity, and high cost. Hence, the discovery and development of novel multi-targeted agents to attenuate the dysregulated signaling in cancer [...] Read more.

Multiple dysregulated signaling pathways are implicated in the pathogenesis of cancer. The conventional therapies used in cancer prevention/treatment suffer from low efficacy, considerable toxicity, and high cost. Hence, the discovery and development of novel multi-targeted agents to attenuate the dysregulated signaling in cancer is of great importance. In recent decades, phytochemicals from dietary and medicinal plants have been successfully introduced as alternative anticancer agents due to their ability to modulate numerous oncogenic and oncosuppressive signaling pathways. Rutin (also known as rutoside, quercetin-3-O-rutinoside and sophorin) is an active plant-derived flavonoid that is widely distributed in various vegetables, fruits, and medicinal plants, including asparagus, buckwheat, apricots, apples, cherries, grapes, grapefruit, plums, oranges, and tea. Rutin has been shown to target various inflammatory, apoptotic, autophagic, and angiogenic signaling mediators, including nuclear factor-κB, tumor necrosis factor-α, interleukins, light chain 3/Beclin, B cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein, caspases, and vascular endothelial growth factor. A comprehensive and critical analysis of the anticancer potential of rutin and associated molecular targets amongst various cancer types has not been performed previously. Accordingly, the purpose of this review is to present an up-to-date and critical evaluation of multiple cellular and molecular mechanisms through which the anticancer effects of rutin are known to be exerted. The current challenges and limitations as well as future directions of research are also discussed. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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21 pages, 1551 KiB

Open AccessReview

Stable Isotope Tracing Metabolomics to Investigate the Metabolic Activity of Bioactive Compounds for Cancer Prevention and Treatment

by Feroza K. Choudhury, G. Lavender Hackman, Alessia Lodi and Stefano Tiziani

Cancers 2020, 12(8), 2147; https://doi.org/10.3390/cancers12082147 - 03 Aug 2020

Cited by 5 | Viewed by 5518

Abstract

A major hallmark of cancer is the metabolic reprogramming of cancer cells to fuel tumor growth and proliferation. Various plant-derived bioactive compounds efficiently target the metabolic vulnerabilities of cancer cells and exhibit potential as emerging therapeutic agents. Due to their safety and common [...] Read more.

A major hallmark of cancer is the metabolic reprogramming of cancer cells to fuel tumor growth and proliferation. Various plant-derived bioactive compounds efficiently target the metabolic vulnerabilities of cancer cells and exhibit potential as emerging therapeutic agents. Due to their safety and common use as dietary components, they are also ideal for cancer prevention. However, to render their use as efficient as possible, the mechanism of action of these phytochemicals needs to be well characterized. Stable isotope tracing is an essential technology to study the molecular mechanisms by which nutraceuticals modulate and target cancer metabolism. The use of positionally labeled tracers as exogenous nutrients and the monitoring of their downstream metabolites labeling patterns enable the analysis of the specific metabolic pathway activity, via the relative production and consumption of the labeled metabolites. Although stable isotope tracing metabolomics is a powerful tool to investigate the molecular activity of bioactive compounds as well as to design synergistic nutraceutical combinations, this methodology is still underutilized. This review aims to investigate the research efforts and potentials surrounding the use of stable isotope tracing metabolomics to examine the metabolic alterations mediated by bioactive compounds in cancer. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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21 pages, 1157 KiB

Open AccessReview

Potentiality, Limitations, and Consequences of Different Experimental Models to Improve Photodynamic Therapy for Cancer Treatment in Relation to Antiangiogenic Mechanism

by Martin Majerník, Rastislav Jendželovský and Peter Fedoročko

Cancers 2020, 12(8), 2118; https://doi.org/10.3390/cancers12082118 - 30 Jul 2020

Cited by 6 | Viewed by 2595

Abstract

The relevance of experimentally gained information represents a long-term debating issue in the field of molecular biology research. The loss of original conditions in the in vitro environment affects various biological mechanisms and cellular interactions. Consequently, some biochemical mechanisms are lost or critically [...] Read more.

The relevance of experimentally gained information represents a long-term debating issue in the field of molecular biology research. The loss of original conditions in the in vitro environment affects various biological mechanisms and cellular interactions. Consequently, some biochemical mechanisms are lost or critically altered. Analyses in these modified conditions could, therefore, distort the relevancy of experimentally gained information. In some cases, the similarities with original conditions are so small that utilization of simpler in vitro models seems impossible, or could occur in a very limited way. To conclude, the study of more complex phenomena places higher demands on the complexity of the experimental model. The latest information highlights the fact that the tumor angiogenesis mechanism has very complex features. This complexity can be associated with a wide range of angiogenic factors expressed by a variety of malignant and non-malignant cells. Our article summarizes the results from various experimental models that were utilized to analyze a photodynamic therapy effect on tumor angiogenic mechanisms. Additionally, based on the latest information, we present the most important attributes and limitations of utilized experimental models. We also evaluate the essential problems associated with angiogenic mechanism induction after photodynamic therapy application. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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81 pages, 1333 KiB

Open AccessReview

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

by Andrea M. Tomko, Erin G. Whynot, Lee D. Ellis and Denis J. Dupré

Cancers 2020, 12(7), 1985; https://doi.org/10.3390/cancers12071985 - 21 Jul 2020

Cited by 103 | Viewed by 27059

Abstract

In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings. Cannabinoids have been suggested and shown to be effective in the [...] Read more.

In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings. Cannabinoids have been suggested and shown to be effective in the treatment of various conditions. In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis. However, the therapeutic use of cannabinoids is currently limited to the treatment of symptoms and pain associated with chemotherapy, while their potential use as cytotoxic drugs in chemotherapy still requires validation in patients. Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions. The potential anti-cancer effects of cannabinoids, terpenes and flavonoids, present in cannabis, are explored in this literature review. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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25 pages, 2599 KiB

Open AccessReview

Coumarins and Coumarin-Related Compounds in Pharmacotherapy of Cancer

by Esra Küpeli Akkol, Yasin Genç, Büşra Karpuz, Eduardo Sobarzo-Sánchez and Raffaele Capasso

Cancers 2020, 12(7), 1959; https://doi.org/10.3390/cancers12071959 - 19 Jul 2020

Cited by 251 | Viewed by 12582

Abstract

Cancer is one of the most common causes of disease-related deaths worldwide. Despite the discovery of many chemotherapeutic drugs that inhibit uncontrolled cell division processes for the treatment of various cancers, serious side effects of these drugs are a crucial disadvantage. In addition, [...] Read more.

Cancer is one of the most common causes of disease-related deaths worldwide. Despite the discovery of many chemotherapeutic drugs that inhibit uncontrolled cell division processes for the treatment of various cancers, serious side effects of these drugs are a crucial disadvantage. In addition, multi-drug resistance is another important problem in anticancer treatment. Due to problems such as cytotoxicity and drug resistance, many investigations are being conducted to discover and develop effective anticancer drugs. In recent years, researchers have focused on the anticancer activity coumarins, due to their high biological activity and low toxicity. Coumarins are commonly used in the treatment of prostate cancer, renal cell carcinoma and leukemia, and they also have the ability to counteract the side effects caused by radiotherapy. Both natural and synthetic coumarin derivatives draw attention due to their photochemotherapy and therapeutic applications in cancer. In this review, a compilation of various research reports on coumarins with anticancer activity and investigation and a review of structure-activity relationship studies on coumarin core are presented. Determination of important structural features around the coumarin core may help researchers to design and develop new analogues with a strong anticancer effect and reduce the potential side effects of existing therapeutics. Full article

(This article belongs to the Special Issue Medicinal Plants and Their Active Ingredients in Cancer)

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