Targeting Thymidylate Synthase Enhances the Chemosensitivity of Triple-Negative Breast Cancer Towards 5-FU-Based Combinatorial Therapy.

Autor:	Haritha NH; Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India., Nawab A; Department of Anatomy and Cell Biology, Cancer and Genetics Research Complex, University of Florida, Gainesville, FL, United States., Vijayakurup V; Department of Anatomy and Cell Biology, Cancer and Genetics Research Complex, University of Florida, Gainesville, FL, United States., Anto NP; The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel., Liju VB; Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India., Alex VV; Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India., Amrutha AN; Department of Biotechnology and Microbiology, Kannur University, Kannur, India., Aiswarya SU; Department of Biotechnology, University of Calicut, Malappuram, India., Swetha M; Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India., Vinod BS; Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India., Sundaram S; Department of Pathology, Government Medical College, Kottayam, India., Guijarro MV; Department of Anatomy and Cell Biology, Cancer and Genetics Research Complex, University of Florida, Gainesville, FL, United States., Herlevich T; Department of Anatomy and Cell Biology, Cancer and Genetics Research Complex, University of Florida, Gainesville, FL, United States., Krishna A; Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India., Nestory NK; Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India., Bava SV; Department of Biotechnology, University of Calicut, Malappuram, India., Sadasivan C; Department of Biotechnology and Microbiology, Kannur University, Kannur, India., Zajac-Kaye M; Department of Anatomy and Cell Biology, Cancer and Genetics Research Complex, University of Florida, Gainesville, FL, United States., Anto RJ; Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2021 Jul 15; Vol. 11, pp. 656804. Date of Electronic Publication: 2021 Jul 15 (Print Publication: 2021).
DOI:	10.3389/fonc.2021.656804
Abstrakt:	Background: The ongoing treatment modalities for breast cancer (BC) primarily rely on the expression status of ER, PR and HER-2 receptors in BC tissues. Our strategy of chemosensitization provides new insights to counter chemoresistance, a major obstacle that limits the benefits of chemotherapy of mammary cancers. Methods: By utilizing a murine breast cancer model employing NSG mice bearing orthotopic triple-negative breast cancer (TNBC) xenografts, we have evaluated the ability of phytochemical curcumin in chemosensitizing BC to 5-Fluorouracil (5-FU) chemotherapy and the differential modulations of cellular events in response to this strategy, independent of their receptor status. Results: A significant synergistic antitumor potential was observed in the murine model with a sub-optimal dose treatment of 5-FU plus curcumin, as evaluated by a reduction in the tumor-related parameters. We authenticated the pivotal role of thymidylate synthase (TS) in regulating the 5-FU-curcumin synergism using the TNBC pre-clinical model. Our study also confirmed the pharmacological safety of this chemotherapeutic plus phytoactive combination using acute and chronic toxicity studies in Swiss albino mice. Subsequently, the molecular docking analysis of curcumin binding to TS demonstrated the affinity of curcumin towards the cofactor-binding site of TS, rather than the substrate-binding site, where 5-FU binds. Our concomitant in vivo and in silico evidence substantiates the superior therapeutic index of this combination. Conclusion: This is the first-ever pre-clinical study portraying TS as the critical target of combinatorial therapy for mammary carcinomas and therefore we recommend its clinical validation, especially in TNBC patients, who currently have limited therapeutic options. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Haritha, Nawab, Vijayakurup, Anto, Liju, Alex, Amrutha, Aiswarya, Swetha, Vinod, Sundaram, Guijarro, Herlevich, Krishna, Nestory, Bava, Sadasivan, Zajac-Kaye and Anto.)
Databáze:	MEDLINE
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