title: Interleukin-24 overcomes temozolomide resistance and enhances cell death by down-regulation of O6-methylguanine-DNA methyltransferase in human melanoma cells.
abstract: Melanoma 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.
authors.affiliation: Introgen Therapeutics, 2250 Holcombe Boulevard, Houston, TX 77030, USA. m.zheng@introgen.com
authors.forename: Mingzhong
authors.initials: M
authors.lastname: Zheng
authors.forename: Dora
authors.initials: D
authors.lastname: Bocangel
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Ramesh
authors.forename: Suhendan
authors.initials: S
authors.lastname: Ekmekcioglu
authors.forename: Nancy
authors.initials: N
authors.lastname: Poindexter
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grimm
authors.forename: Sunil
authors.initials: S
authors.lastname: Chada
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D016923:Cell Death; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007378:Interleukins / Q000502:physiology*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099180:Interleukin-24
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D007378:Interleukins; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53; D000099180:Interleukin-24