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

摘要

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 (AP-1), has been implicated in both the maintenance and 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 ribonuclease chemotherapeutic drug ranpirnase to inhibit cell growth. Because the thiazolidinedione (TZD) anti-diabetic 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 knock-down 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 knock-down cells, demonstrating 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.