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Science 10 September 1999:
Vol. 285. no. 5434, pp. 1733 - 1737
DOI: 10.1126/science.285.5434.1733
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Reports

A Chemical Inhibitor of p53 That Protects Mice from the Side Effects of Cancer Therapy

Pavel G. Komarov, 12* Elena A. Komarova, 1* Roman V. Kondratov, 15 Konstantin Christov-Tselkov, 3 John S. Coon, 2 Mikhail V. Chernov, 4 Andrei V. Gudkov 1dagger

Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Because these effects are in part determined by p53-mediated apoptosis, temporary suppression of p53 has been suggested as a therapeutic strategy to prevent damage of normal tissues during treatment of p53-deficient tumors. To test this possibility, a small molecule was isolated for its ability to reversibly block p53-dependent transcriptional activation and apoptosis. This compound, pifithrin-alpha , protected mice from the lethal genotoxic stress associated with anticancer treatment without promoting the formation of tumors. Thus, inhibitors of p53 may be useful drugs for reducing the side effects of cancer therapy and other types of stress associated with p53 induction.

1 Department of Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
2 Department of Pathology, Rush Presbyterian St. Luke's Medical Center, Chicago, IL 60612, USA.
3 Department of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA.
4 Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
5 Quark Biotech, Pleasanton, CA 94566, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: gudkov{at}uic.edu

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J. Am. Soc. Nephrol. 16, 2615-2625
   Abstract »    Full Text »    PDF »
Loss of Tumor Suppressor p53 Decreases PTEN Expression and Enhances Signaling Pathways Leading to Activation of Activator Protein 1 and Nuclear Factor {kappa}B Induced by UV Radiation.
J. Wang, W. Ouyang, J. Li, L. Wei, Q. Ma, Z. Zhang, Q. Tong, J. He, and C. Huang (2005)
Cancer Res. 65, 6601-6611
   Abstract »    Full Text »    PDF »
The p53 Inhibitor Pifithrin-{alpha} Is a Potent Agonist of the Aryl Hydrocarbon Receptor.
M. S. Hoagland, E. M. Hoagland, and H. I. Swanson (2005)
J. Pharmacol. Exp. Ther. 314, 603-610
   Abstract »    Full Text »    PDF »
Lipopolysaccharide Prevents Doxorubicin-Induced Apoptosis in RAW 264.7 Macrophage Cells by Inhibiting p53 Activation.
F. Hassan, S. Islam, M. M. Mu, H. Ito, N. Koide, I. Mori, T. Yoshida, and T. Yokochi (2005)
Mol. Cancer Res. 3, 373-379
   Abstract »    Full Text »    PDF »
New Approaches and Therapeutics Targeting Apoptosis in Disease.
U. Fischer and K. Schulze-Osthoff (2005)
Pharmacol. Rev. 57, 187-215
   Abstract »    Full Text »    PDF »
Transcriptional Blockade Induces p53-dependent Apoptosis Associated with Translocation of p53 to Mitochondria.
Y. Arima, M. Nitta, S. Kuninaka, D. Zhang, T. Fujiwara, Y. Taya, M. Nakao, and H. Saya (2005)
J. Biol. Chem. 280, 19166-19176
   Abstract »    Full Text »    PDF »
Ectopic mTERT expression in mouse embryonic stem cells does not affect differentiation but confers resistance to differentiation- and stress-induced p53-dependent apoptosis.
M. K. Lee, M. P. Hande, and K. Sabapathy (2005)
J. Cell Sci. 118, 819-829
   Abstract »    Full Text »    PDF »
Apoptosis in the development and treatment of cancer.
R. Gerl and D. L. Vaux (2005)
Carcinogenesis 26, 263-270
   Abstract »    Full Text »    PDF »
Deregulation of Cell Proliferation by Polycyclic Aromatic Hydrocarbons in Human Breast Carcinoma MCF-7 Cells Reflects Both Genotoxic and Nongenotoxic Events.
M. Pliskova, J. Vondracek, B. Vojtesek, A. Kozubik, and M. Machala (2005)
Toxicol. Sci. 83, 246-256
   Abstract »    Full Text »    PDF »
Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope.
J.-L. Perfettini, M. Castedo, R. Nardacci, F. Ciccosanti, P. Boya, T. Roumier, N. Larochette, M. Piacentini, and G. Kroemer (2005)
J. Exp. Med. 201, 279-289
   Abstract »    Full Text »    PDF »
Drugging the Cancer Kinome: Progress and Challenges in Developing Personalized Molecular Cancer Therapeutics.
P. WORKMAN (2005)
Cold Spring Harb Symp Quant Biol 70, 499-515
   Abstract »    PDF »
How tissues respond to damage at the cellular level: orchestration by transforming growth factor-{beta} (TGF-{beta}).
M H Barcellos-Hoff (2005)
Br. J. Radiol. Supplement_27, 123-127
   Abstract »    Full Text »    PDF »
Survivin and p53 Modulate Quercetin-induced Cell Growth Inhibition and Apoptosis in Human Lung Carcinoma Cells.
P.-C. Kuo, H.-F. Liu, and J.-I Chao (2004)
J. Biol. Chem. 279, 55875-55885
   Abstract »    Full Text »    PDF »
Regulation of Steroidogenesis by p53 in Macaque Granulosa Cells and H295R Human Adrenocortical Cells.
M. Cherian-Shaw, R. Das, C. A. VandeVoort, and C. L. Chaffin (2004)
Endocrinology 145, 5734-5744
   Abstract »    Full Text »    PDF »
Role of p53 in cisplatin-induced tubular cell apoptosis: dependence on p53 transcriptional activity.
M. Jiang, X. Yi, S. Hsu, C.-Y. Wang, and Z. Dong (2004)
Am J Physiol Renal Physiol 287, F1140-F1147
   Abstract »    Full Text »    PDF »


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