This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Turkson, J. Articles by Jove, R. Search for Related Content PubMed PubMed Citation Articles by Turkson, J. Articles by Jove, R.

¹ Molecular Oncology, ² Immunology and ³ Drug Discovery Programs, H. Lee Moffitt Cancer Center & Research Institute; and Departments of ⁴ Interdisciplinary Oncology, ⁵ Biochemistry and Molecular Biology, ⁶ Pathology, ⁷ Chemistry, and ⁸ College of Public Health, University of South Florida, Tampa, Florida

Requests for reprints: James Turkson, Molecular Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, SRB 22214, Tampa, FL 33612. Phone: 813-745-6725; Fax: 813-632-1436. E-mail: turksonj{at}moffitt.usf.edu

DNA-alkylating agents that are platinum complexes induce apoptotic responses and have wide application in cancer therapy. The potential for platinum compounds to modulate signal transduction events that contribute to their therapeutic outcome has not been extensively examined. Among the signal transducer and activator of transcription (STAT) proteins, Stat3 activity is frequently up-regulated in many human tumors. Various lines of evidence have established a causal role for aberrant Stat3 activity in malignant transformation and provided validation for its targeting in the development of small-molecule inhibitors as novel cancer therapeutics. We report here that platinum-containing compounds disrupt Stat3 signaling and suppress its biological functions. The novel platinum (IV) compounds, CPA-1, CPA-7, and platinum (IV) tetrachloride block Stat3 activity in vitro at low micromolar concentrations. In malignant cells that harbor constitutively activated Stat3, CPA-1, CPA-7, and platinum (IV) tetrachloride inhibit cell growth and induce apoptosis in a manner that reflects the attenuation of persistent Stat3 activity. By contrast, cells that do not contain persistent Stat3 activity are marginally affected or are not affected by these compounds. Moreover, CPA-7 induces the regression of mouse CT26 colon tumor, which correlates with the abrogation of persistent Stat3 activity in tumors. Thus, the modulation of oncogenic signal transduction pathways, such as Stat3, may be one of the key molecular mechanisms for the antitumor effects of platinum (IV)–containing complexes.

Key Words: Stat3 • drug target • inhibitors • platinum compounds • proliferation • apoptosis

Grant support: National Cancer Institute grants CA78038, CA55652,and CA82533 from the NIH.

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.

⁹ G. Niu, et al. Role of Stat3 in regulating p53 expression and function, submitted manuscript, 2004.

¹⁰ M.A. Blaskovich et al. submitted manuscript, 2004.

Received 4/29/04; revised 9/27/04; accepted 10/15/04.