Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway
- J. E. Kravchenko*,†,
- G. V. Ilyinskaya*,†,‡,
- P. G. Komarov§,¶,
- L. S. Agapova*,‡,
- D. V. Kochetkov*,†,
- E. Strom§,¶,
- E. I. Frolova‖,
- I. Kovriga‖,
- A. V. Gudkov*,**,
- E. Feinstein§, and
- P. M. Chumakov*,†,††
- *Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195;
- †Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Street 32, Moscow 119991, Russia;
- ‡Cancer Research Center, Kashirskoye Shosse 24, Moscow 115478, Russia;
- §Quark Biotech, Inc., 6501 Dumbarton Circle, Fremont, CA 94555; and
- ‖Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, Moscow 117997, Russia
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Communicated by George R. Stark, Lerner Research Institute NB21, Cleveland, OH, March 4, 2008 (received for review December 20, 2007)
Abstract
Identification of unique features of cancer cells is important for defining specific and efficient therapeutic targets. Mutant p53 is present in nearly half of all cancer cases, forming a promising target for pharmacological reactivation. In addition to being defective for the tumor-suppressor function, mutant p53 contributes to malignancy by blocking a p53 family member p73. Here, we describe a small-molecule RETRA that activates a set of p53-regulated genes and specifically suppresses mutant p53-bearing tumor cells in vitro and in mouse xenografts. Although the effect is strictly limited to the cells expressing mutant p53, it is abrogated by inhibition with RNAi to p73. Treatment of mutant p53-expressing cancer cells with RETRA results in a substantial increase in the expression level of p73, and a release of p73 from the blocking complex with mutant p53, which produces tumor-suppressor effects similar to the functional reactivation of p53. RETRA is active against tumor cells expressing a variety of p53 mutants and does not affect normal cells. The results validate the mutant p53–p73 complex as a promising and highly specific potential target for cancer therapy.
Footnotes
- ††To whom correspondence should be addressed. E-mail: chumakp{at}ccf.org
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Author contributions: J.E.K., G.V.I., and P.G.K. contributed equally to this work; A.V.G., E.F., and P.M.C. designed research; J.E.K., G.V.I., P.G.K., L.S.A., D.V.K., E.S., E.I.F., I.K., and P.M.C. performed research; P.G.K. and P.M.C. analyzed data; and P.M.C. wrote the paper.
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↵ ¶Present address: Cleveland BioLabs, Inc., 11000 Cedar Avenue, Cleveland, OH 44106.
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↵**Present address: Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0802091105/DCSupplemental.
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Freely available online through the PNAS open access option.
- © 2008 by The National Academy of Sciences of the USA
