New Approaches for Prostate Cancer Combination Therapy

Abstract

Abstract : The mechanisms underlying the antineoplastic actions of NSAIDs remain poorly understood. We started deciphering now the mechanisms by which NSAIDs induce programmed cell death and growth arrest in cancer. In this report we show that induction of the pro-apoptotic cytokine melanoma differentiation associated gene-7/Interleukin-24 (MDA-7/IL-24) and the expression of growth arrest and DNA damage inducible (GADD) 45 alpha and gamma by several NSAIDs is an essential step for G2/M growth arrest and apoptosis induction of cancer cells and inhibition of tumor growth in vivo. MDA-7/IL24 dependent upregulation of GADD45 alpha and gamma expression is sufficient for cancer cell apoptosis, since inhibition of GADD45 alpha and gamma by small interfering RNA abrogates apoptosis and growth arrest induction by the NSAID, blocks JNK activation and restores CDC2 kinase activity. Our results establish MDA-7/IL-24 and GADD45 alpha and gamma as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells. Pharmacological inhibitors of NF-kappa B have a potent effect in apoptosis induction of prostate cancer cells as well as in combination with NSAIDs. This new treatment could be then tested in combination of inhibitors of NF-kappa B pathway which are already in clinical trials.