Authors: YiWei Zhang, Qi Zhang, Shelya X. Zeng, Yu Zhang, Lindsey D. Mayo and Hua Lu

YiWei Zhang

Department of Biochemistry and Molecular Biology and Tulane Cancer Center; Tulane University School of Medicine; New Orleans, LA USA

Qi Zhang

Department of Biochemistry and Molecular Biology and Tulane Cancer Center; Tulane University School of Medicine; New Orleans, LA USA

Shelya X. Zeng

Department of Biochemistry and Molecular Biology and Tulane Cancer Center; Tulane University School of Medicine; New Orleans, LA USA

Yu Zhang

Department of Obstetrics and Gynecology; Xiangya Hospital; Central South University; Changsha, China

Lindsey D. Mayo

Herman B. Wells Center for Pediatric Research; Department of Pediatrics; Indiana University School of Medicine-Simon Cancer Center; Indianapolis, IN USA

Hua Lu

Corresponding author: hlu2@tulane.edu
Department of Biochemistry and Molecular Biology and Tulane Cancer Center; Tulane University School of Medicine; New Orleans, LA USA

Abstract:
Several proteins have been suggested in promoting tumor formation in numerous human tissues by inactivating the tumor suppressor p53. This has generated interest in the development of small molecules to block these inhibitors of p53 and to regain p53 activity. Recently, we identified a small molecule, Inauhzin, which can inhibit SIRT1 activity and activate p53. SIRT1 is a deacetylase that deacetylates p53 and facilitates Mdm2 mediated p53 destabilization. In this study, we tested if combining Inauhzin with Nutlin-3, an inhibitor of MDM2-p53 binding, might synergistically activate p53 to suppress tumor growth. Indeed, at lower doses, combination of Inauhzin and Nutlin-3 exhibited a synergistic effect on inhibiting cell growth and promoting apoptosis in human colon and lung cancer cell lines in a p53-dependent fashion. Minimal effects were observed with treatment of either compound alone. Using a xenograft tumor model, we also showed a synergistic effect with both compounds. Thus, to fully regain p53 activity, targeting its multiple inhibitory proteins might be a better approach. Our study provides evidence supporting this concept for achieving better therapeutic efficacy in tumors that possess wild type p53.

Received: March 14, 2012; Accepted: May 22, 2012

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