2-(Diarylalkyl)aminobenzothiazole derivatives induce autophagy and apoptotic death through SIRT inhibition and P53 activation In MCF7 breast cancer cells

Abstract

Sirtuins (SIRTs) are multifunctional proteins that exhibit a wide range of substrate preferences and cellular localizations. They are reliant on NAD⁺ and are essential for the regulation of several cellular functions. The SIRT proteins play important role towards tumor survival and resistance mechanisms in tumor cells. Therefore, molecules targeting SIRT proteins gained significant recognition in cancer research. In this work, we explored the anticancer property, potential and mode of action of 2-(diarylalkyl)aminobenzothiazole derivatives on MCF7 human breast cancer cells. Our studies established that 2-(diarylalkyl)aminobenzothiazole derivatives 1-((6-chlorobenzo[d]thiazol-2-ylamino)(3,4-dichlorophenyl)methyl)naphthalen-2-ol (7ab) and 1-((6-chlorobenzo[d]thiazol-2-ylamino)(4-bromophenyl)methyl)naphthalen-2-ol (7ba) treatment in a dose dependent manner drastically lowered the cell proliferation in MCF7 cells and the IC50 values of 7ab and 7ba was found to be 11.4 µM and 9.6 µM at 24 hr in these cells. Docking and molecular dynamic simulation studies further revealed that 7ab and 7ba show significant binding with SIRT1 protein. Consistently, treatment with 7ab and 7ba reduced the expression levels of SIRT1 protein while increasing acetylation of p53, a known SIRT protein target in MCF-7 cells. We observed that SIRT1inhibition was associated with activation of p53, an essential protein for apoptotic cell death, in MCF-7 cell lines. Furthermore, 7ab and 7ba treatment induced LC3-II expression and vacuole formation in the cytoplasm leading to autophagic cell death. Our findings together reveal the plausible cellular targets and specificity of these new small molecules as SIRT inhibitors, which increase p53 acetylation and suppress the proliferation of MCF-7 human breast cancer cells by triggering autophagic and apoptotic cell death.