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Identification of phytoestrogens as sirtuin inhibitor against breast cancer: Multitargeted approach
Venkateswarlu Kojja1, Vanitha Rudraram2, Bhanukiran Kancharla1
1Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, India.
Abstract:
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.
Insights
Coumestrol, a plant-derived phytoestrogen, effectively inhibits sirtuin proteins in breast cancer cells. This study highlights coumestrol as a promising novel therapeutic strategy for combating breast cancer resistance.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Breast cancer is a leading cause of cancer deaths globally, with high resistance to current therapies necessitating novel treatment strategies.
- Sirtuins, a class of signaling proteins, are implicated in cellular processes and represent a potential therapeutic target for breast cancer.
- Phytoestrogens, plant-derived compounds with estrogen-like properties, have demonstrated anticancer activities.
Purpose of the Study:
- To investigate the potential of various phytoestrogens as sirtuin inhibitors for breast cancer treatment.
- To evaluate the efficacy of coumestrol, a specific phytoestrogen, against breast cancer cell lines.
- To elucidate the mechanism of action of coumestrol in inhibiting breast cancer progression.
Main Methods:
- In-silico molecular docking and molecular dynamic studies were performed to assess phytoestrogen binding affinity to sirtuin proteins 1-3.
- In-vitro studies included cell proliferation assays, colony formation assays, flow cytometry for reactive oxygen species (ROS) analysis, and western blot analysis for SIRT-1 expression.
- Breast cancer cell lines (MCF-7 and MDAMB-231) were utilized for in-vitro experiments.
Main Results:
- Molecular docking identified coumestrol as having high binding energy with sirtuin proteins 1-3.
- Molecular dynamics confirmed stable and high-affinity interactions between coumestrol and sirtuin binding sites.
- Coumestrol significantly reduced breast cancer cell proliferation and colony formation, induced intracellular ROS, and decreased SIRT-1 expression.
Conclusions:
- In-silico and in-vitro data strongly suggest that coumestrol exhibits sirtuin inhibitory activity.
- Coumestrol demonstrates significant anticancer effects against breast cancer cell lines.
- Phytoestrogen coumestrol represents a promising novel therapeutic candidate for breast cancer treatment targeting sirtuins.
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