Sirtinol, a SIRT1 inhibitor, inhibits the EMT and metastasis of 4T1 breast cancer cells and impacts the tumor microenvironment.

Abstract

Introduction: The impact of epigenetic drugs on metastasis and the immunological microenvironment is poorly understood. In this study, we looked at how sirtinol, a SIRT1 inhibitor, affected epithelial-mesenchymal transition (EMT), metastasis, and the immune cells.

Materials and methods: In vitro experiments were carried out using tumor conditioned medium (TCM). For in vivo experiments, sirtinol was administered i.p. in tumor bearing BALB/c mice at a dose of 2 mg/kg body weight either alone or in combination with cisplatin. Estimation of cytokines was carried out using ELISA or ELIspot. Estimation of different markers was done using flow cytometry or western blot.

Results: Sirtinol, a SIRT1 inhibitor, was found to be cytotoxic to 4T1 breast cancer cells with no synergistic effects with cisplatin, both under in vitro and in vivo conditions (p < 0.05). Sirtinol significantly reduced cancer cell metastasis to the spleen which was supported by in vitro findings such as decreased vimentin expression and cell mobility in migration and wound healing assays (p < 0.01). Studies on the effects of 4T1 tumor-conditioned medium on spleen cells indicated changes in T cell proliferation as well as differentiation (p < 0.01). In tumor bearing mice, spleen cells showed elevated IFN-γ secretion, increased CD11b⁺ cells, and decreased T cells (p < 0.01). This was reversed by sirtinol as well as the combination treatment, which may also have contributed to metastasis inhibition (p < 0.01).

Conclusion: Sirtinol, a SIRT1 inhibitor inhibits EMT and metastasis of 4T1 breast cancer cells and also has an impact on the immune microenvironment.