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Mechanism and Targets of Resveratrol and Its Analogs on the Reorganization of the Tumor Microenvironment

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

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 20268

Special Issue Editors

Dr. Tze-chen Hsieh

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, New York Medical College, Room 133, Valhalla, NY 10595, USA
Interests: chemoprevention; immunotherapy; bioinformatics
Dr. Joseph M. Wu

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, USA
Interests: chemoprevention; cardioprotection; senescence and aging

Special Issue Information

Dear Colleagues,

Resveratrol is a widely studied grape polyphenol present in red wine, red grape skin, and peanuts. Numerous studies of resveratrol have been conducted and its health effects have mainly focused on the prevention of cardiovascular disease, cancer, and aging. The anti-tumor activity of resveratrol was first identified in 1997 and was substantiated by a flurry of scientific reports in the ensuing years. Recently, a plethora of studies have investigated the impact of resveratrol on the immune response, in particular on the T cells vis-à-vis metabolic reprogramming and/or upregulation of IFN-γ expression. These results suggest that resveratrol can simultaneously target tumor and host immune cells and reorganize the tumor microenvironment so as to change host anti-tumor immunity impacting the efficacy of immune-therapy, e.g., anti-PD-(L)1. Currently, the mechanism and targets of resveratrol and its analogs on the reorganization of the tumor microenvironment, host–tumor interplay, and host anti-tumor immune modulation remain to be elucidated.

Reviews and original research papers covering “Mechanism and Targets of Resveratrol and Its Analogs on the Reorganization of the Tumor Microenvironment” are welcome for inclusion in this Special Issue of Molecules. Specific topics include:

  • the tumor microenvironment;
  • metabolic reprogramming;
  • tumor or immune cell death/survival;
  • tumor–host immune cell interplay;
  • nucleus–mitochondria inter-organelle communication.

Dr. Tze-chen Hsieh
Dr. Joseph M. Wu
Guest Editors

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Keywords

  • cellular/biochemical mechanisms of action
  • metabolic reprogramming
  • host immune response
  • natural and synthetic derivatives of resveratrol
  • cellular targets of resveratrol and derivatives.

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Published Papers (4 papers)

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Research

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13 pages, 2979 KiB  
Article
Resveratrol Enhances Inhibition Effects of Cisplatin on Cell Migration and Invasion and Tumor Growth in Breast Cancer MDA-MB-231 Cell Models In Vivo and In Vitro
by Meng-Die Yang, Yang Sun, Wen-Jun Zhou, Xiao-Zheng Xie, Qian-Mei Zhou, Yi-Yu Lu and Shi-Bing Su
Molecules 2021, 26(8), 2204; https://doi.org/10.3390/molecules26082204 - 12 Apr 2021
Cited by 50 | Viewed by 4880
Abstract
Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) [...] Read more.
Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) cell viability, migration, and invasion in vivo and in vitro. In vitro, MTS assays showed that resveratrol combined with cisplatin inhibits cell viability as a concentration-dependent manner, and produced synergistic effects (CI < 1). Transwell assay showed that the combined treatment inhibits TGF-β1-induced cell migration and invasion. Immunofluorescence assays confirmed that resveratrol upregulated E-cadherin expression and downregulated vimentin expression. Western blot assay demonstrated that resveratrol combined with cisplatin significantly reduced the expression of fibronectin, vimentin, P-AKT, P-PI3K, P-JNK, P-ERK, Sma2, and Smad3 induced by TGF-β1 (p < 0.05), and increased the expression of E-cadherin (p < 0.05), respectively. In vivo, resveratrol enhanced tumor growth inhibition and reduced body weight loss and kidney function impairment by cisplatin in MDA231 xenografts, and significantly reduced the expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, P-ERK, and NF-κB in tumor tissues (p < 0.05). These results indicated that resveratrol combined with cisplatin inhibits the viability of breast cancer MDA231 cells synergistically, and inhibits MDA231 cells invasion and migration through Epithelial-mesenchymal transition (EMT) approach, and resveratrol enhanced anti-tumor effect and reduced side of cisplatin in MDA231 xenografts. The mechanism may be involved in the regulations of PI3K/AKT, JNK, ERK and NF-κB expressions. Full article
(This article belongs to the Special Issue Mechanism and Targets of Resveratrol and Its Analogs on the Reorganization of the Tumor Microenvironment)
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21 pages, 3798 KiB  
Article
Resveratrol Suppresses Cross-Talk between Colorectal Cancer Cells and Stromal Cells in Multicellular Tumor Microenvironment: A Bridge between In Vitro and In Vivo Tumor Microenvironment Study
by Constanze Buhrmann, Parviz Shayan, Aranka Brockmueller and Mehdi Shakibaei
Molecules 2020, 25(18), 4292; https://doi.org/10.3390/molecules25184292 - 18 Sep 2020
Cited by 54 | Viewed by 4296
Abstract
The interaction between tumor cells and the tumor microenvironment (TME) is an important process for the development of tumor malignancy. Modulation of paracrine cross-talk could be a promising strategy for tumor control within the TME. The exact mechanisms of multi-targeted compound resveratrol are [...] Read more.
The interaction between tumor cells and the tumor microenvironment (TME) is an important process for the development of tumor malignancy. Modulation of paracrine cross-talk could be a promising strategy for tumor control within the TME. The exact mechanisms of multi-targeted compound resveratrol are not yet fully understood. Whether resveratrol can modulate paracrine signal transduction-induced malignancy in the multicellular-TME of colorectal cancer cells (CRC) was investigated. An in vitro model with 3D-alginate HCT116 cells in multicellular-TME cultures (fibroblast cells, T-lymphocytes) was used to elucidate the role of TNF-β, Sirt1-ASO and/or resveratrol in the proliferation, invasion and cancer stem cells (CSC) of CRC cells. We found that multicellular-TME, similar to TNF-β-TME, promoted proliferation, colony formation, invasion of CRC cells and enabled activation of CSCs. However, after co-treatment with resveratrol, the malignancy of multicellular-TME reversed to HCT116. In addition, resveratrol reduced the secretion of T-lymphocyte/fibroblast (TNF-β, TGF-β3) proteins, antagonized the T-lymphocyte/fibroblast-promoting NF-κB activation, NF-κB nuclear translocation and thus the expression of NF-κB-promoting biomarkers, associated with proliferation, invasion and survival of CSCs in 3D-alginate cultures of HCT116 cells induced by TNF-β- or multicellular-TME, but not by Sirt1-ASO, indicating the central role of this enzyme in the anti-tumor function of resveratrol. Our results suggest that in vitro multicellular-TME promotes crosstalk between CRC and stromal cells to increase survival, migration of HCT116 and the resveratrol/Sirt1 axis suppresses this loop by modulating paracrine agent secretion and NF-κB signaling. Fibroblasts and T-lymphocytes are promising targets for resveratrol in the prevention of CRC metastasis. Full article
(This article belongs to the Special Issue Mechanism and Targets of Resveratrol and Its Analogs on the Reorganization of the Tumor Microenvironment)
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Review

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12 pages, 1642 KiB  
Review
Recent Advancements on Immunomodulatory Mechanisms of Resveratrol in Tumor Microenvironment
by Gagan Chhabra, Chandra K. Singh, Deeba Amiri, Neha Akula and Nihal Ahmad
Molecules 2021, 26(5), 1343; https://doi.org/10.3390/molecules26051343 - 3 Mar 2021
Cited by 31 | Viewed by 4581
Abstract
Immunomodulation of the tumor microenvironment is emerging as an important area of research for the treatment of cancer patients. Several synthetic and natural agents are being investigated for their ability to enhance the immunogenic responses of immune cells present in the tumor microenvironment [...] Read more.
Immunomodulation of the tumor microenvironment is emerging as an important area of research for the treatment of cancer patients. Several synthetic and natural agents are being investigated for their ability to enhance the immunogenic responses of immune cells present in the tumor microenvironment to impede tumor cell growth and dissemination. Among them, resveratrol, a stilbenoid found in red grapes and many other natural sources, has been studied extensively. Importantly, resveratrol has been shown to possess activity against various human diseases, including cancer. Mechanistically, resveratrol has been shown to regulate an array of signaling pathways and processes involving oxidative stress, inflammation, apoptosis, and several anticancer effects. Furthermore, recent research suggests that resveratrol can regulate various cellular signaling events including immune cell regulation, cytokines/chemokines secretion, and the expression of several other immune-related genes. In this review, we have summarized recent findings on resveratrol’s effects on immune regulatory cells and associated signaling in various cancer types. Numerous immunomodulatory effects of resveratrol suggest it may be useful in combination with other cancer therapies including immunotherapy for effective cancer management. Full article
(This article belongs to the Special Issue Mechanism and Targets of Resveratrol and Its Analogs on the Reorganization of the Tumor Microenvironment)
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25 pages, 993 KiB  
Review
Resveratrol and Tumor Microenvironment: Mechanistic Basis and Therapeutic Targets
by Wamidh H. Talib, Ahmad Riyad Alsayed, Faten Farhan and Lina T. Al Kury
Molecules 2020, 25(18), 4282; https://doi.org/10.3390/molecules25184282 - 18 Sep 2020
Cited by 40 | Viewed by 5836
Abstract
Resveratrol (3,4′,5 trihydroxystilbene) is a naturally occurring non-flavonoid polyphenol. It has various pharmacological effects including antioxidant, anti-diabetic, anti-inflammatory and anti-cancer. Many studies have given special attention to different aspects of resveratrol anti-cancer properties and proved its high efficiency in targeting multiple cancer hallmarks. [...] Read more.
Resveratrol (3,4′,5 trihydroxystilbene) is a naturally occurring non-flavonoid polyphenol. It has various pharmacological effects including antioxidant, anti-diabetic, anti-inflammatory and anti-cancer. Many studies have given special attention to different aspects of resveratrol anti-cancer properties and proved its high efficiency in targeting multiple cancer hallmarks. Tumor microenvironment has a critical role in cancer development and progression. Tumor cells coordinate with a cast of normal cells to aid the malignant behavior of cancer. Many cancer supporting players were detected in tumor microenvironment. These players include blood and lymphatic vessels, infiltrating immune cells, stromal fibroblasts and the extracellular matrix. Targeting tumor microenvironment components is a promising strategy in cancer therapy. Resveratrol with its diverse biological activities has the capacity to target tumor microenvironment by manipulating the function of many components surrounding cancer cells. This review summarizes the targets of resveratrol in tumor microenvironment and the mechanisms involved in this targeting. Studies discussed in this review will participate in building a solid ground for researchers to have more insight into the mechanism of action of resveratrol in tumor microenvironment. Full article
(This article belongs to the Special Issue Mechanism and Targets of Resveratrol and Its Analogs on the Reorganization of the Tumor Microenvironment)
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