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Research Articles: Therapeutics, Targets, and Development

Reactivation of p53 by a specific MDM2 antagonist (MI-43) leads to p21-mediated cell cycle arrest and selective cell death in colon cancer

¹ Comprehensive Cancer Center and Departments of ² Internal Medicine, ³ Pharmacology, ⁴ Medicinal Chemistry, and ⁵ Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Shaomeng Wang, Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109. Phone: 734-615-0362; Fax: 734-647-9647. E-mail: shaomeng{at}umich.edu

Abstract

MDM2 oncoprotein binds directly to the p53 tumor suppressor and inhibits its function in cancers retaining wild-type p53. Blocking this interaction using small molecules is a promising approach to reactivate p53 function and is being pursued as a new anticancer strategy. The spiro-oxindole MI-43, a small-molecule inhibitor of the MDM2-p53 interaction, was designed and examined for its cellular mechanism of action and therapeutic potential in colon cancer. MI-43 binds to MDM2 protein with a K_i value of 18 nmol/L and is 300 times more potent than a native p53 peptide. MI-43 blocks the intracellular MDM2-p53 interaction and induces p53 accumulation in both normal and cancer cells, with wild-type p53 without causing p53 phosphorylation. Induction of p53 leads to modulation of the expression of p53 target genes, including up-regulation of p21 and MDM2 in normal primary human cells and in colon cancer cells with wild-type p53. Using HCT-116 isogenic colon cancer cell lines differing only in p53 status or RNA interference to knockdown expression of p53 in the RKO colon cancer cell line, we show that the cell growth inhibition and cell death induction by MI-43 is p53 dependent. Furthermore, induction of cell cycle arrest by MI-43 is dependent on p53 and p21. In normal cells, MI-43 induces cell cycle arrest but not apoptosis. This study suggests that p53 activation by a potent and specific spiro-oxindole MDM2 antagonist may represent a promising therapeutic strategy for the treatment of colon cancer and should be further evaluated in vivo and in the clinic. [Mol Cancer Ther 2008;7(6):1533–42]

Grant support: National Cancer Institute/NIH grant R01CA121279, University of Michigan Prostate Cancer SPORE P50CA069568, Leukemia and Lymphoma Society, Prostate Cancer Foundation, and Ascenta Therapeutics (S. Wang) and University of Michigan Cancer Center grant P30CA046592.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 2/ 6/08; revised 3/26/08; accepted 4/ 9/08.