Identification of phytoestrogens as sirtuin inhibitor against breast cancer: Multitargeted approach

• Published in: Computational biology and chemistry Vol. 112; p. 108168
• Main Authors: Kojja, Venkateswarlu, Rudraram, Vanitha, Kancharla, Bhanukiran, Siva, Hemalatha, Tangutur, Anjana Devi, Nayak, Prasanta Kumar
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2024
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Coumestrol; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Molecular docking; Molecular Docking Simulation; Molecular Structure; Phytoestrogens; Phytoestrogens - chemistry; Phytoestrogens - pharmacology; SIRT inhibitors; Sirtuins; Sirtuins - antagonists & inhibitors; Sirtuins - chemistry; Sirtuins - metabolism; Structure-Activity Relationship; Sirtuins; Phytoestrogens; ILE; COU; Breast cancer; WB; MTT; PHE; TYR; Molecular docking; DMEM; SIRT inhibitors; HIS; Coumestrol; PE; ALA; MD; ROS; DCFDA; ASP; SIRT
• ISSN: 1476-9271; 1476-928X; 1476-928X
• DOI: 10.1016/j.compbiolchem.2024.108168

Despite progress in diagnosis and treatment strategies, breast cancer remains a primary risk to female health as indicated by second most cancer-deaths globally caused by this cancer. High risk mutation is linked to prognosis of breast cancer. Due to high resistance of breast cancer against current therapies, there is necessity of novel treatment strategies. Sirtuins are signaling proteins belonging to histone deacetylase class III family, known to control several cellular processes. Therefore, targeting sirtuins could be one of the approaches to treat breast cancer. Several plants synthesize phytoestrogens which exhibit structural and physiological similarities to estrogens and have been recognized to possess anticancer activity. In our study, we investigated several phytoestrogens for sirtuin inhibition by conducting molecular docking studies, and in-vitro studies against breast cancer cell lines. In molecular docking studies, we identified coumestrol possessing high binding energy with sirtuin proteins 1–3 as compared to other phytoestrogens. The molecular dynamic studies showed stable interaction of ligand and protein with higher affinity at sirtuin proteins 1–3 binding sites. In cell proliferation assay and colony formation assay using breast cancer cell lines (MCF-7 and MDAMB-231) coumestrol caused significant reduction in cell proliferation and number of colonies formed. Further, the flow cytometric analysis showed that coumestrol induces intracellular reactive oxygen species and the western blot analysis revealed reduction in the level of SIRT-1 expression in breast cancer cell lines. In conclusion, in-silico data and in-vitro studies suggest that the phytoestrogen coumestrol has sirtuin inhibitory activity against breast cancer. [Display omitted] •The study demonstrated and investigated phytoestrogens sirtuins binding and its anticancer activity against breast cancer.•The in-silico studies determined the most effective binding agents with sirtuins.•MD studies revealed protein ligand stability of phytoestrogen with sirtuins.•Phytoestrogens reduced the cell viability, increased cellular ROS level, and inhibited the sirtuin protein expression.•Phytoestrogens were proven as an anticancer agent and effective sirtuin inhibition observed in breast cancer cells.