PT  - JOURNAL ARTICLE
AU  - Zheng, Mingzhong
AU  - Bocangel, Dora
AU  - Ramesh, Rajagopal
AU  - Ekmekcioglu, Suhendan
AU  - Poindexter, Nancy
AU  - Grimm, Elizabeth A.
AU  - Chada, Sunil
TI  - Interleukin-24 overcomes temozolomide resistance and enhances cell death by down-regulation of <em>O</em><sup>6</sup>-methylguanine-DNA methyltransferase in human melanoma cells
AID  - 10.1158/1535-7163.MCT-08-0516
DP  - 2008 Dec 01
TA  - Molecular Cancer Therapeutics
PG  - 3842--3851
VI  - 7
IP  - 12
4099  - http://mct.aacrjournals.org/content/7/12/3842.short
4100  - http://mct.aacrjournals.org/content/7/12/3842.full
SO  - Mol Cancer Ther2008 Dec 01; 7
AB  - 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. [Mol Cancer Ther 2008;7(12):3842–51]