SMALL MOLECULE MODULATORS OF SIRT1 ACTIVITY ACTIVATE P53 AND SUPPRESS TUMOR GROWTH

摘要

Although -50 % of all types of human cancers harbor wild type TP 53, this p53 tumor suppressor is often deactivated through a concerted action by its abnormally elevated suppressors, MDM2, MDMX, or SIRT1. Reported herein are small molecules such as Inauhzin that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53 -dependent apoptosis of human cancer cells without causing apparently genotoxic stress. Moreover, Inauhzin stabilizes p53 by increasing p53 acetylation and preventing MDM2 -mediated ubiquitylation of p53 in cells, though not directly in vitro. Remarkably, Inauhzin inhibits cell proliferation, induces senescence and tumor-specific apoptosis, and represses the growth of xenograft tumors derived from p53- harboring H460 and HCT116 cells without causing apparent toxicity to normal tissues and the tumor-bearing SCID mice. As reported herein, Inauhzin is an anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.