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Bioactive Phytochemicals for Cancer Prevention and Treatment II

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 53067

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Special Issue Editors

Prof. Dr. Sanjay K. Srivastava

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Guest Editor

Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, 1718 Pine Street, Abilene, TX 79601, USA
Interests: development of phytochemicals for cancer prevention and therapeutics; targeting STAT-3, NF-kB, HER2, MCL-1, AKT/FOXO, GLI1/2, and related signaling pathways with agents such as capsaicin, piperlongumine, penfluridol, isothiocyanates, diindolylmethane, panabinostat, cucurbitacin B, and deguelin in pancreatic, ovarian, breast, melanoma, and brain cancer; drug repurposing
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Sung-Hoon Kim

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Guest Editor

Cancer Molecular Target Herbal Research Lab, College of Korean Medicine, Kyunghee University, Seoul 02447, Republic of Korea
Interests: cancer biology; tumor immunology; inflammation; angiogenesis; metastasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Plants have been an important source of bioactive phytochemicals since historic times. Phytochemicals are synthesized by plants as their defensive mechanisms. Several epidemiological studies indicate an inverse correlation between the intake of specific plant foods and cancer incidence. Thousands of phytochemicals have been identified to date, but only a few have been explored in depth for their beneficial roles. Phytochemicals available from dietary plant sources can be classified based on their chemical structures. For example, isothiocyanates, indoles, carotenoids, flavonoids, isoflavones, and terpenoids are some of the major classes studied for their anticancer effects. Phytochemicals are considered to be advantageous over the current chemotherapeutic options available. This is because cancer etiology involves multiple mechanisms, and phytochemicals, being pleiotropic, can counter more procarcinogenic mechanisms. Moreover, being a component of dietary plants, phytochemicals are also relatively nontoxic and generally have broader safety windows. Combination therapy is evitable in clinical practice. Several phytochemicals have been shown to enhance the effects of chemotherapeutic drugs. This Special Issue has been envisaged to document studies on well-known phytochemicals and their role in cancer prevention. The articles in this issue come from eminent researchers in the field of cancer chemoprevention from all around the world. This Issue will be beneficial to all the basic, clinical, and applied researchers and physicians interested in cancer chemoprevention and chemotherapeutics.

Prof. Sanjay K. Srivastava
Prof. Dr. Sung-Hoon Kim
Guest Editors

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Keywords

Cancer
Chemoprevention
Phytochemicals
Dietary agents
Functional foods
Bioactive agents
Anticancer
Molecular mechanism
Signaling mechanism
Cell cycle
Apoptosis
Combination therapy
Therapeutics

Published Papers (11 papers)

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Research

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18 pages, 3514 KiB

Open AccessArticle

Arctigenin Attenuates Breast Cancer Progression through Decreasing GM-CSF/TSLP/STAT3/β-Catenin Signaling

by Hui Shi, Luping Zhao, Xinlin Guo, Runping Fang, Hui Zhang, Guanjun Dong, Jia Fu, Fenglian Yan, Junfeng Zhang, Zhaochen Ning, Qun Ma, Zhihua Li, Chunxia Li, Jun Dai, Chuanping Si and Huabao Xiong

Int. J. Mol. Sci. 2020, 21(17), 6357; https://doi.org/10.3390/ijms21176357 - 02 Sep 2020

Cited by 15 | Viewed by 3687 | Correction

Abstract

Invasive breast cancer is highly regulated by tumor-derived cytokines in tumor microenvironment. The development of drugs that specifically target cytokines are promising in breast cancer treatment. In this study, we reported that arctigenin, a bioactive compound from Arctium lappa L., could decrease tumor-promoting cytokines GM-CSF, MMP-3, MMP-9 and TSLP in breast cancer cells. Arctigenin not only inhibited the proliferation, but also the invasion and stemness of breast cancer cells via decreasing GM-CSF and TSLP. Mechanistically, arctigenin decreased the promoter activities of GM-CSF and TSLP via reducing the nuclear translocation of NF-κB p65 which is crucial for the transcription of GM-CSF and TSLP. Furthermore, arctigenin-induced depletion of GM-CSF and TSLP inhibited STAT3 phosphorylation and β-catenin signaling resulting in decreased proliferation, invasion and stemness of breast cancer cells in vitro and in vivo. Our findings provide new insights into the mechanism by which tumor-promoting cytokines regulate breast cancer progression and suggest that arctigenin is a promising candidate for cytokine-targeted breast cancer therapy. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment II)

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19 pages, 4754 KiB

Open AccessArticle

Anticancer and Antiangiogenic Activities of Novel α-Mangostin Glycosides in Human Hepatocellular Carcinoma Cells via Downregulation of c-Met and HIF-1α

by Sung Min Kim, Jang Mi Han, Tuoi Thi Le, Jae Kyung Sohng and Hye Jin Jung

Int. J. Mol. Sci. 2020, 21(11), 4043; https://doi.org/10.3390/ijms21114043 - 05 Jun 2020

Cited by 14 | Viewed by 3273

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Therefore, exploring effective anticancer agents and their modes of action is essential for the prevention and treatment of HCC. Glycosylation can significantly improve the physicochemical and biological properties of small molecules, such as high solubility, stability increase, and lower toxicity. In the present study, for the first time, we evaluated the anticancer and antiangiogenic activities of α-mangostin-3-O-β-D-2-deoxyglucopyranoside (Man-3DG) and α-mangostin 6-O-β-D-2-deoxyglucopyranoside (Man-6DG), glycosides of α-mangostin, against human HCC cells. Our results demonstrated that Man-3DG and Man-6DG significantly suppressed the growth of three different HCC cells (Hep3B, Huh7, and HepG2) as well as the migration of Hep3B cells. Furthermore, they induced cell cycle arrest in the G0/G1 phases and apoptotic cell death by regulating apoptosis-related proteins of mitochondria in Hep3B cells. Noticeably, Man-3DG and Man-6DG also caused autophagy, while co-treatment of the α-mangostin glycosides with an autophagy inhibitor 3-MA enhanced the inhibitory effect on Hep3B cell growth in comparison to single agent treatment. Moreover, Man-3DG and Man-6DG inhibited the c-Met signaling pathway that plays a critical role in the pathogenesis of HCC. Furthermore, the α-mangostin glycosides decreased Hep3B cell-induced angiogenesis in vitro through the downregulation of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Notably, Man-6DG more effectively inhibited the growth, tumorsphere formation, and expression of cancer stemness regulators compared to α-mangostin and Man-3DG in 3D spheroid-cultured Hep3B cells. These findings suggest that the α-mangostin glycosides might be promising anticancer agents for HCC treatment with superior pharmacological properties than the parent molecule α-mangostin. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment II)

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18 pages, 1675 KiB

Open AccessArticle

Arctigenin Enhances the Cytotoxic Effect of Doxorubicin in MDA-MB-231 Breast Cancer Cells

by Kyu-Shik Lee, Min-Gu Lee, Yun-Suk Kwon and Kyung-Soo Nam

Int. J. Mol. Sci. 2020, 21(8), 2997; https://doi.org/10.3390/ijms21082997 - 23 Apr 2020

Cited by 16 | Viewed by 5238

Abstract

Several reports have described the anti-cancer activity of arctigenin, a lignan extracted from Arctium lappa L. Here, we investigated the effect of arctigenin (ATG) on doxorubicin (DOX)-induced cell death using MDA-MB-231 human breast cancer cells. The results showed that DOX-induced cell death was enhanced by ATG/DOX co-treatment in a concentration-dependent manner and that this was associated with increased DOX uptake and the suppression of multidrug resistance-associated protein 1 (MRP1) gene expression in MDA-MB-231 cells. ATG enhanced DOX-induced DNA damage and decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the expressions of RAD51 and survivin. Cell death caused by ATG/DOX co-treatment was mediated by the nuclear translocation of apoptosis inducing factor (AIF), reductions in cellular and mitochondrial Bcl-2 and Bcl-xL, and increases in mitochondrial BAX levels. However, caspase-3 and -7 did not participate in DOX/ATG-induced cell death. We also found that DOX/ATG-induced cell death was linked with activation of the p38 signaling pathway and suppressions of the phosphorylations and expressions of Akt and c-Jun N-terminal kinase. Taken together, these results show that ATG enhances the cytotoxic activity of DOX in MDA-MB-231 human breast cancer cells by inducing prolonged p21 expression and p38-mediated AIF-dependent cell death. In conclusion, our findings suggest that ATG might alleviate the side effects and improve the therapeutic efficacy of DOX. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment II)

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11 pages, 1188 KiB

Open AccessArticle

(+)-Limonene 1,2-Epoxide-Loaded SLNs: Evaluation of Drug Release, Antioxidant Activity, and Cytotoxicity in an HaCaT Cell Line

by Eliana B. Souto, Aleksandra Zielinska, Selma B. Souto, Alessandra Durazzo, Massimo Lucarini, Antonello Santini, Amélia M. Silva, Atanas G. Atanasov, Conrado Marques, Luciana N. Andrade and Patricia Severino

Int. J. Mol. Sci. 2020, 21(4), 1449; https://doi.org/10.3390/ijms21041449 - 20 Feb 2020

Cited by 66 | Viewed by 4237

Abstract

In this work, we developed a solid lipid nanoparticle (SLN) formulation with (+)-limonene 1,2-epoxide and glycerol monostearate (Lim-SLNs), stabilized with Poloxamer^® 188 in aqueous dispersion to modify the release profile of the loaded monoterpene derivative. We also evaluated the role of SLNs in lipid peroxidation and cytotoxicity in a spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (the HaCaT cell line). For the cell viability assay, the colorimetric 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used. Lim-SLNs with a loading capacity and encapsulation efficiency of 0.39% and 63%, respectively, were produced by high pressure homogenization. A mean particle size of 194 ± 3.4 nm and polydispersity index of 0.244 were recorded for the loaded Lim-SLNs, as compared to 203 ± 1.5 nm (PI 0.213) for the non-loaded (blank) SLNs. The loading of the monoterpene derivative into glycerol monostearate SLNs fitted into the zero-order kinetics, and ameliorated both lipid peroxidation and cytotoxicity in a keratinocyte cell line. A promising formulation for antioxidant and anti-tumoral activities is here proposed. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment II)

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16 pages, 4467 KiB

Open AccessArticle

Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression

by Laura Pietrovito, Marta Iozzo, Marina Bacci, Elisa Giannoni and Paola Chiarugi

Int. J. Mol. Sci. 2020, 21(3), 787; https://doi.org/10.3390/ijms21030787 - 25 Jan 2020

Cited by 21 | Viewed by 7133

Abstract

Endo-, phyto- and synthetic cannabinoids have been proposed as promising anti-cancer agents able to impair cancer cells’ behavior without affecting their non-transformed counterparts. However, cancer outcome depends not only on cancer cells’ activity, but also on the stromal cells, which coevolve with cancer cells to sustain tumor progression. Here, we show for the first time that cannabinoid treatment impairs the activation and the reactivity of cancer-associated fibroblasts (CAFs), the most represented stromal component of prostate tumor microenvironment. Using prostate cancer-derived CAFs, we demonstrated that WIN 55-212.2 mesylate, a synthetic full agonist of cannabinoid receptors (CBs) 1 and 2, downregulates α-smooth muscle actin and matrix metalloprotease-2 expression, and it inhibits CAF migration, essential features to ensure the activated and reactive CAF phenotype. Furthermore, by impairing stromal reactivity, WIN 55-212.2 mesylate also negatively affects CAF-mediated cancer cells’ invasiveness. Using selective antagonists of CBs, we proved that CAFs response to WIN 55-212.2 mesylate is mainly mediated by CB₂. Finally, we suggest that endocannabinoids self-sustain both prostate tumor cells migration and CAFs phenotype by an autocrine loop. Overall, our data strongly support the use of cannabinoids as anti-tumor agents in prostate cancer, since they are able to simultaneously strike both cancer and stromal cells. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment II)

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13 pages, 1806 KiB

Open AccessArticle

Licochalcone A Inhibits BDNF and TrkB Gene Expression and Hypoxic Growth of Human Tumor Cell Lines

by Michitsune Arita, Junichi Koike, Nobuji Yoshikawa, Motonari Kondo and Hiromichi Hemmi

Int. J. Mol. Sci. 2020, 21(2), 506; https://doi.org/10.3390/ijms21020506 - 13 Jan 2020

Cited by 7 | Viewed by 2880

Abstract

Hypoxic cellular proliferation is a common feature of tumor cells and is associated with tumor progression. Therefore, the inhibition of hypoxic cellular proliferation is expected to regulate malignancy processes. Licochalcone A (LicA) is known to show inhibitory effects on cell growth in normoxia, but it is unclear whether LicA exerts similar effects in hypoxia. Here, we studied the inhibitory activity of LicA in the hypoxic cellular proliferation of tumor cells and its molecular mechanism using human cell lines derived from various tumors including neuroblastoma and colorectal cancer. LicA inhibited cell growth at a 50% inhibitory concentration between 7.0 and 31.1 µM in hypoxia. LicA significantly suppressed hypoxic induction of tropomyosin receptor kinase B (TrkB) gene expression at the transcription level. LicA also downregulated mRNA levels of the TrkB high-affinity ligand brain-derived neurotrophic factor, but not neurotrophin-4, another TrkB ligand, or glyceraldehyde-3-phosphate dehydrogenase, indicating that the inhibitory activity of LicA is selective. Since both LicA-treatment and TrkB-knockdown decreased activation of protein kinase B in hypoxia, LicA exerts its inhibitory effect against hypoxic cell growth through inhibition of the TrkB-AKT axis. These results suggest that LicA has therapeutic potential for malignant tumors including neuroblastoma and colorectal cancer. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment II)

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Review

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19 pages, 645 KiB

Open AccessReview

Phytochemicals in Gynecological Cancer Prevention

by Marta Woźniak, Rafał Krajewski, Sebastian Makuch and Siddarth Agrawal

Int. J. Mol. Sci. 2021, 22(3), 1219; https://doi.org/10.3390/ijms22031219 - 26 Jan 2021

Cited by 29 | Viewed by 4902

Abstract

Gynecological cancer confers an enormous burden among women worldwide. Accumulating evidence points to the role of phytochemicals in preventing cervical, endometrial, and ovarian cancer. Experimental studies emphasize the chemopreventive and therapeutic potential of plant-derived substances by inhibiting the early stages of carcinogenesis or improving the efficacy of traditional chemotherapeutic agents. Moreover, a number of epidemiological studies have investigated associations between a plant-based diet and cancer risk. This literature review summarizes the current knowledge on the phytochemicals with proven antitumor activity, emphasizing their effectiveness and mechanism of action in gynecological cancer. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment II)

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30 pages, 3217 KiB

Open AccessReview

Natural Agents Targeting Mitochondria in Cancer

by Shalini Mani, Geeta Swargiary and Keshav K. Singh

Int. J. Mol. Sci. 2020, 21(19), 6992; https://doi.org/10.3390/ijms21196992 - 23 Sep 2020

Cited by 42 | Viewed by 6446

Abstract

Mitochondria are the key energy provider to highly proliferating cancer cells, and are subsequently considered one of the critical targets in cancer therapeutics. Several compounds have been studied for their mitochondria-targeting ability in cancer cells. These studies’ outcomes have led to the invention of “mitocans”, a category of drug known to precisely target the cancer cells’ mitochondria. Based upon their mode of action, mitocans have been divided into eight classes. To date, different synthetic compounds have been suggested to be potential mitocans, but unfortunately, they are observed to exert adverse effects. Many studies have been published justifying the medicinal significance of large numbers of natural agents for their mitochondria-targeting ability and anticancer activities with minimal or no side effects. However, these natural agents have never been critically analyzed for their mitochondria-targeting activity. This review aims to evaluate the various natural agents affecting mitochondria and categorize them in different classes. Henceforth, our study may further support the potential mitocan behavior of various natural agents and highlight their significance in formulating novel potential anticancer therapeutics. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment II)

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17 pages, 1355 KiB

Open AccessReview

Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer

by Yan Bian, Juntong Wei, Changsheng Zhao and Guorong Li

Int. J. Mol. Sci. 2020, 21(2), 684; https://doi.org/10.3390/ijms21020684 - 20 Jan 2020

Cited by 53 | Viewed by 7445

Abstract

Cancer is one of the most serious diseases endangering human health. In view of the side effects caused by chemotherapy and radiotherapy, it is necessary to develop low-toxic anti-cancer compounds. Polyphenols are natural compounds with anti-cancer properties and their application is a considerable choice. Pro-senescence therapy is a recently proposed anti-cancer strategy and has been shown to effectively inhibit cancer. It is of great significance to clarify the mechanisms of polyphenols on tumor suppression by inducing senescence. In this review, we delineated the characteristics of senescent cells, and summarized the mechanisms of polyphenols targeting tumor microenvironment and inducing cancer cell senescence for cancer prevention and therapy. Although many studies have shown that polyphenols effectively inhibit cancer by targeting senescence, it warrants further investigation in preclinical and clinical studies. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment II)

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26 pages, 967 KiB

Open AccessReview

Phytochemicals for the Prevention and Treatment of Gastric Cancer: Effects and Mechanisms

by Qian-Qian Mao, Xiao-Yu Xu, Ao Shang, Ren-You Gan, Ding-Tao Wu, Atanas G. Atanasov and Hua-Bin Li

Int. J. Mol. Sci. 2020, 21(2), 570; https://doi.org/10.3390/ijms21020570 - 16 Jan 2020

Cited by 42 | Viewed by 5591

Abstract

Gastric cancer is the fifth most common cancer, and the third most prevalent cause of cancer-related deaths in the world. Voluminous evidence has demonstrated that phytochemicals play a critical role in the prevention and management of gastric cancer. Most epidemiological investigations indicate that the increased intake of phytochemicals could reduce the risk of gastric cancer. Experimental studies have elucidated the mechanisms of action, including inhibiting cancer cell proliferation, inducing apoptosis and autophagy, and suppressing angiogenesis as well as cancer cell metastasis. These mechanisms have also been related to the inhibition of Helicobacter pylori and the modulation of gut microbiota. In addition, the intake of phytochemicals could enhance the efficacy of anticancer chemotherapeutics. Moreover, clinical studies have illustrated that phytochemicals have the potential for the prevention and the management of gastric cancer in humans. To provide an updated understanding of relationships between phytochemicals and gastric cancer, this review summarizes the effects of phytochemicals on gastric cancer, highlighting the underlying mechanisms. This review could be helpful for guiding the public in preventing gastric cancer through phytochemicals, as well as in developing functional food and drugs for the prevention and treatment of gastric cancer. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment II)

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