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Research Articles: Therapeutics, Targets, and Development

A novel combination: ranpirnase and rosiglitazone induce a synergistic apoptotic effect by down-regulating Fra-1 and Survivin in cancer cells

Departments of ¹ Pathology and ² Medicine and Nursing, University of Vermont, Burlington, Vermont

Requests for reprints: Maria E. Ramos-Nino, Department of Pathology, University of Vermont, HSRF 216, Burlington, VT 05405. Phone: 802-656-0395; Fax: 802-656-8892. E-mail: Maria.Ramos{at}uvm.edu

Abstract

Accumulating evidence supports the idea that two known phosphatidylinositol 3'-kinase (PI3K) downstream proteins, Fra-1 and Survivin, are potential targets for cancer therapy. Increased expression of Fra-1, a Fos family member of the transcription factor activator protein-1, has been implicated in both the maintenance and the progression of the transformed state of several cancer cells. In addition, high Survivin expression in tumors correlates with more aggressive behavior, lower response to chemotherapeutic drugs, and shortened survival time. Previously, we reported that, in malignant mesothelioma cells with increased PI3K activity, small-molecule inhibitors of the PI3K/AKT pathway acted cooperatively with the amphibian RNase chemotherapeutic drug ranpirnase to inhibit cell growth. Because the thiazolidinedione antidiabetic drug rosiglitazone targets the PI3K/AKT pathway, we investigated the effect of the combination of these two drugs in cell survival in several cancer cell lines. We show here that the combination of ranpirnase and rosiglitazone synergistically decreases cell viability and increases cell apoptosis in several cancer cell lines. Cell killing is associated with decreased Fra-1 and Survivin expression and knockdown of Fra-1 increases cell killing by ranpirnase in a dose-dependent manner but not by rosiglitazone. The drug combination does not have a synergistic effect on killing in Fra-1 knockdown cells, showing that Fra-1 modulation accounts in part for the synergism. The novel drug combination of ranpirnase and rosiglitazone is a promising combination to treat cancers with increased PI3K-dependent Fra-1 expression or Survivin. [Mol Cancer Ther 2008;7(7):1871–9]

Grant support: NIH grants K01 CA104159 (M.E. Ramos-Nino) and K24 DK068380 (B. Littenberg).

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.

Note: M.E. Ramos-Nino designed and did the research. B. Littenberg contributed to the analysis and critical reading of the article.

³ http://www.ncbi.nlm.nih.gov

Received 3/31/08; accepted 4/23/08.