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Interleukin-24 overcomes temozolomide resistance and enhances cell death by down-regulation of O6-methylguanine-DNA methyltransferase in human melanoma cells Zheng M; Bocangel D; Ramesh R; Ekmekcioglu S; Poindexter N; Grimm EA; Chada SMol Cancer Ther 2008[Dec]; 7 (12): 3842-51Melanoma is the most malignant of skin cancers, highly resistant to chemotherapy and radiotherapy. Temozolomide, a promising new derivative of dacarbazine, is currently being tested for treatment of metastatic melanoma. Resistance to alkylating agents such as temozolomide correlates with increased expression of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Interleukin-24 (IL-24; mda-7) is a tumor suppressor cytokine that selectively inhibits tumor cell growth by inducing apoptosis and cell cycle arrest in melanoma cell lines and solid tumors. This tumor-selective activity has been observed in multiple preclinical animal models and in clinical trials. In this study, we analyzed the ability of Ad-IL-24 and its protein product, IL-24, to overcome temozolomide resistance in human melanoma cells. We have shown that Ad-IL-24 via exogenous IL-24 protein induces combinatorial synergy of temozolomide-induced cell killing in temozolomide-resistant melanoma cells by inhibition of MGMT. Neutralizing antibodies against IL-24 or its receptors significantly blocked the apoptotic activity of IL-24 + MGMT treatment. We show that accumulation of functional p53 is essential for IL-24-induced down-regulation of MGMT. Using either MGMT small interfering RNA, p53 small interfering RNA, or a p53 dominant-negative mutant to block MGMT protein expression resulted in increased sensitization to temozolomide. However, MGMT blockade in combination with IL-24 + temozolomide resulted in loss of combinatorial synergy, indicating that MGMT expression is required for the reversal of temozolomide resistance in melanoma cells. This study shows that IL-24 can play a significant role in overcoming temozolomide resistance and that the clinical efficacy of temozolomide may be improved by using a biochemotherapy combination with IL-24.|*Drug Resistance, Neoplasm[MESH]|*Gene Expression Regulation, Neoplastic[MESH]|Antineoplastic Agents, Alkylating/*pharmacology[MESH]|Cell Death[MESH]|Cell Line, Tumor[MESH]|Dacarbazine/*analogs & derivatives/pharmacology[MESH]|Dose-Response Relationship, Drug[MESH]|Down-Regulation[MESH]|Flow Cytometry[MESH]|Humans[MESH]|Interleukins/*physiology[MESH]|Melanoma/*drug therapy/*metabolism[MESH]|O(6)-Methylguanine-DNA Methyltransferase/*metabolism[MESH]|Skin Neoplasms/*drug therapy/*metabolism[MESH]|Temozolomide[MESH]|Tumor Suppressor Protein p53/metabolism[MESH] |
