PRIMA-1met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms

// Xiao-Lan Li 1, 2, * , Jianbiao Zhou 1, * , Zit-Liang Chan 1 , Jing-Yuan Chooi 1 , Zhi-Rong Chen 2 , Wee-Joo Chng 1, 3, 4 1 Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Republic of Singapore 2 Department of Gastroenterology, Suzhou Municipal Hospital (Eastern), Suzhou City, Jiangsu Province, 215001, P.R. China 3 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Republic of Singapore 4 Department of Hematology-Oncology, National University Hospital, Singapore 119228, Republic of Singapore * These authors have contributed equally to this work Correspondence to: Wee-Joo Chng, e-mail: mdccwj@nus.edu.sg Zhi-Rong Chen, e-mail: czr88188@163.com Keywords: colorectal cancer (CRC), p53, tumor suppressor gene (TSG), PRIMA-1 met , targeted therapy Received: July 14, 2015      Accepted: September 17, 2015      Published: October 01, 2015 ABSTRACT PRIMA-1 met (APR-246) is a methylated derivative and structural analog of PRIMA-1 (p53 re-activation and induction of massive apoptosis). PRIMA-1 met has been reported to restore both the wild type (wt) structure and function of mutant p53. Here, we show that PRIMA-1 met is highly effective at limiting the growth of CRC cells regardless of p53 status. However, PRIMA-1 met induces robust apoptosis only in CRC cells with mutant p53. Upregulation of Noxa, a proapoptotic molecule, is crucial for PRIMA-1 met mediated activity. In human xenograft model of disease, PRIMA-1 met effectively suppresses CRC tumor growth. Our results uncover distinct mechanisms of PRIMA-1 met in CRC with different p53 status, thus providing a mechanistic rationale to evaluate the clinical efficacy of PRIMA-1 met in CRC patients with different p53 status.