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lüll Melanoma differentiation associated gene-7, mda-7/interleukin-24, induces apoptosis in prostate cancer cells by promoting mitochondrial dysfunction and inducing reactive oxygen species Lebedeva IV; Su ZZ; Sarkar D; Kitada S; Dent P; Waxman S; Reed JC; Fisher PBCancer Res 2003[Dec]; 63 (23): 8138-44Mda-7/IL-24 (Ad.mda-7) is a novel cytokine gene belonging to the interleukin (IL) 10 gene superfamily. Adenoviral-mediated delivery of mda-7/IL-24 causes growth suppression and apoptosis in a wide spectrum of cancer cells, including prostate, without harming normal cells. We now demonstrate that Ad.mda-7 selectively induces apoptosis in prostate cancer cells by promoting mitochondrial dysfunction and reactive oxygen species (ROS) production. Antioxidants (N-acetyl-L-cysteine and Tiron) and inhibitors of mitochondrial permeability transition (cyclosporine A and bongkrekic acid) inhibit Ad.mda-7-induced mitochondrial dysfunction and apoptosis. Conversely, agents augmenting ROS production (arsenic trioxide, NSC656240, and PK11195) facilitate Ad.mda-7-induced apoptosis. Ectopic expression of Bcl-2 and Bcl-x(L) inhibits mitochondrial changes, ROS production, and apoptosis providing additional support for an association between mitochondrial dysfunction and Ad.mda-7 action. These studies present definitive evidence that changes in mitochondrial function and ROS production are key components associated with selective killing of prostate cancer cells by mda-7/IL-24.|Adenoviridae/genetics[MESH]|Apoptosis/*physiology[MESH]|Cell Line, Tumor[MESH]|Gene Transfer Techniques[MESH]|Genes, Tumor Suppressor/*physiology[MESH]|Humans[MESH]|Interleukins/*genetics[MESH]|Male[MESH]|Mitochondria/*physiology[MESH]|Prostatic Neoplasms/*genetics/metabolism/*pathology[MESH]|Proto-Oncogene Proteins c-bcl-2/biosynthesis/physiology[MESH]|Reactive Oxygen Species/*metabolism[MESH]|bcl-X Protein[MESH] |