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J. Biol. Chem., Vol. 280, Issue 38, 32979-32988, September 23, 2005

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A Novel Platinum Compound Inhibits Constitutive Stat3 Signaling and Induces Cell Cycle Arrest and Apoptosis of Malignant Cells^*

James Turkson1, Shumin Zhang, Linda B. Mora, Audrey Burns¶, Said Sebti¶||, and Richard Jove¶**

From the Molecular Oncology and ^||Drug Discovery Programs, H. Lee Moffitt Cancer Center & Research Institute, and the Departments of Oncology, ^¶Biochemistry and Molecular Biology, and ^**Pathology, University of South Florida College of Medicine, Tampa, Florida 33612

Previous studies have established constitutive activation of Stat3 protein as one of the molecular changes required for tumorigenesis. To develop novel therapeutics for tumors harboring constitutively active Stat3, compounds from the NCI 2000 diversity set were evaluated for inhibition of Stat3 DNA-binding activity in vitro. Of these, a novel platinum (IV) compound, IS3 295, interacted with Stat3 and inhibited its binding to specific DNA-response elements. Further analysis suggested noncompetitive-type kinetics for the inhibition of Stat3 binding to DNA. In human and mouse tumor cell lines with constitutively active Stat3, IS3 295 selectively attenuated Stat3 signaling, thereby inducing cell growth arrest at G₀/G₁ phase and apoptosis. Moreover, in transformed cells, IS3 295 repressed expression of cyclin D₁ and bcl-x_L, two of the known Stat3-regulated genes that are overexpressed in malignant cells, suggesting that IS3 295 mediates anti-tumor cell activity in part by blocking Stat3-mediated sub-version of cell growth and apoptotic signals. Together, our findings provide evidence for the inhibition of Stat3 activity and biological functions by IS3 295 through interaction with Stat3 protein. This study represents a significant advance in small molecule-based approaches to target Stat3 and suggests potential new applications for platinum (IV) complexes as modulators of the Stat3 pathway for cancer therapy.

Received for publication, March 11, 2005 , and in revised form, June 17, 2005.

^* This work was supported by the Charlotte-Geyer Foundation (to J. T.) and NCI Grant CA55652 from the National Institutes of Health (to R. J.). 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.

¹ To whom correspondence should be addressed: BioMolecular Science Center, Dept. of Molecular Biology and Microbiology, University of Central Florida, 12722 Research Pkwy., Orlando, FL 32826. Tel.: 407-823-4812; E-mail: jturkson{at}mail.ucf.edu.

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