Aim: To identify novel inhibitors of SIRT1 and to understand their mechanism of action in hepatocellular carcinoma. Materials & methods: Molecular docking and dynamic simulations were conducted to identify potential SIRT1 inhibitors. The in vitro efficacy of the inhibitors was evaluated by methyl thiazolyl tetrazolium assays, flow cytometry and western blot analysis. Additionally, the in vivo antitumor activity of the inhibitor was evaluated. Results: Tipranavir, a US FDA-approved anti-HIV-1 medication, was found to possess potential as a SIRT1 inhibitor. Tipranavir selectively inhibited HepG2 cell proliferation without causing toxicity to normal human hepatic cells. Additionally, tipranavir treatment resulted in a reduction of SIRT1 expression and induction of apoptosis in HepG2 cells. Furthermore, tipranavir was found to suppress tumorigenesis in a xenograft mouse model and decreased the expression of SIRT1 in vivo. Conclusion: Tipranavir holds desirable potential as a promising therapeutic agent against hepatoma.
Keywords: SIRT1; hepatocellular carcinoma; tipranavir; virtual screening.