A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53

Abstract

Although ∼50% of all types of human cancers harbour wild-type TP53, this p53 tumour suppressor is often deactivated through a concerted action by its abnormally elevated suppressors, MDM2, MDMX or SIRT1. Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress. Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro. Remarkably, INZ inhibits cell proliferation, induces senescence and tumour-specific apoptosis, and represses the growth of xenograft tumours derived from p53-harbouring H460 and HCT116 cells without causing apparent toxicity to normal tissues and the tumour-bearing SCID mice. Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.

L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells

“…Tumor volume (mm 3 ) was calculated as (length  width 2 )/2. 58 Mice were killed 40 days after treatment, and tumors were excised and weighed.…”

Inauhzin(c) Inactivates c-Myc Independently of p53

“…[15][16][17][18]22 However, whether INZ could function to suppress the expression of c-Myc and inhibit lymphoma cell growth remains unknown. To this end, we treated human lymphoma Boston cells with INZ(c), an INZ analog with better potency.…”

“…We previously showed that INZ does not introduce noticeable DNA damage 15 and could sensitize p53-dependent cytotoxicity and tumor suppression of chemotherapeutic agents, such as doxorubicin (Dox). 17 Therefore, we next checked whether INZ(c) could cooperatively target c-Myc expression with doxorubicin, as doxorubicin had been shown to suppress c-Myc expression.…”

“…13,14,[17][18][19][20] Previously, we identified a small molecule called Inauhzin (INZ) that could activate p53 by suppressing SIRT1 activity, leading to cell cycle arrest and apoptosis of cancer cells without introducing detectable DNA damage to cells. 15 Transcriptome analysis of cells treated with INZ showed that over 200 p53 targets were induced by INZ, suggesting INZ is indeed a p53 activator. 16 Also, we showed that INZ could activate p53 synergistically with Nutlin-3, an Mdm2 inhibitor, and sensitize cancer cells to chemotherapeutic drugs, such as cisplatin and doxorubicin.…”

“…17,18 In addition, in xenograft mouse model, INZ treatment reduced tumor size and promoted survival of tumorbearing mice, suggesting INZ suppresses tumorigenesis and could be a potential drug for cancer therapy. 15 Very recently, we found that INZ can cause ribosomal stress by inhibiting cellular IMPDH2 activity and reducing cellular GTP level, consequently decreasing the level of nucleostemin, 19 a nucleolar GTP-binding protein important for rRNA processing. 20,21 This study provides a second mechanism for INZ activation of p53.…”