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PRIMA-1met (APR-246) Inhibits Growth of Colorectal Cancer Cells with Different p53 Status through Distinct Mechanisms. (Oncotarget, Oct 2015)

Li XL1,2, Zhou J1, Chan ZL1, Chooi JY1, Chen ZR2, Chng WJ1,3,4

1 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Department of Gastroenterology, Suzhou Municipal Hospital (Eastern), Suzhou City, Jiangsu Province, 215001, P.R. China.
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.

Abstract:
PRIMA-1met (APR-246) is a methylated derivative and structural analog of PRIMA-1 (p53 re-activation and induction of massive apoptosis). PRIMA-1met has been reported to restore both the wild type (wt) structure and function of mutant p53. Here, we show that PRIMA-1met is highly effective at limiting the growth of CRC cells regardless of p53 status. However, PRIMA-1met induces robust apoptosis only in CRC cells with mutant p53. Upregulation of Noxa, a proapoptotic molecule, is crucial for PRIMA-1met mediated activity. In human xenograft model of disease, PRIMA-1met effectively suppresses CRC tumor growth. Our results uncover distinct mechanisms of PRIMA-1met in CRC with different p53 status, thus providing a mechanistic rationale to evaluate the clinical efficacy of PRIMA-1met in CRC patients with different p53 status.