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Depletion of Mutant p53 and Cytotoxicity of Histone Deacetylase Inhibitors

¹ New York Medical College, Valhalla, New York; ² Cancer Center, Ordway Research Institute, Albany, New York; ³ The Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; ⁴ Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, New Jersey; and ⁵ Department of Radiation Oncology, Harvard Medical School, Charlestown, Massachusetts

Requests for reprints: Mikhail V. Blagosklonny, Cancer Center, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208. Phone: 914-347-2801; Fax: 914-347-2804; E-mail: blagosklonny{at}hotmail.com.

Mutant p53 is a cancer-specific target for pharmacologic intervention. We show that histone deacetylase inhibitors such as FR901228 and trichostatin A completely depleted mutant p53 in cancer cell lines. This depletion was preceded by induction of p53-regulated transcription. In cells with mutant p53 pretreated with histone deacetylase inhibitors, DNA damage further enhanced the p53 trans-function. Furthermore, histone deacetylase inhibitors were preferentially cytotoxic to cells with mutant p53 rather than to cells lacking wild-type p53. We suggest that, by either restoring or mimicking p53 trans-functions, histone deacetylase inhibitors initiate degradation of mutant p53. Because mutant p53 is highly expressed, a sudden restoration of p53-like functions is highly cytotoxic to cells with mutant p53. In a broader perspective, this shows how selectivity may be achieved by targeting a non-cancer-specific target, such as histone deacetylases, in the presence of a cancer-specific alteration, such as mutant p53.

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