Abstract 4354: Celecoxib reduces MGMT expression and potentiates the effect of temozolomide in childhood medulloblastoma

Abstract

Abstract Background: O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that protects DNA from the biological effects of alkylating agents. MGMT has been implicated in resistance to alkylating drugs such as temozolomide used in the clinic against brain tumors. Temozolomide has been shown to be ineffective in tumors expressing MGMT and in medulloblastoma high expression of MGMT is correlated with poor prognosis. Therefore, the demand to find agents that deplete MGMT is warranted. Methods: medulloblastoma cell cytotoxicity of chemotherapeutic drugs in combination with Celecoxib was examined in MGMT positive cell lines using fluorometric microculture cytotoxicity assay. In vivo, nude NMRI mice carrying MGMT positive D283 MED xenografts were treated with celecoxib in combination with temozolomide. For mechanistic studies, western blot and quantitative PCR were used. Results: the clinically available COX-2 inhibitor Celecoxib induced a synergistic or an additive cytotoxic effect in combination with Temozolomide, Cyclophosphamide, Doxorubicin, Irinotecan, Vincristine, Rapamycin or CCI-779 in vitro. In vivo, Celecoxib synergistically potentiates the effect of Temozolomide through downregulation of MGMT expression. Conclusions: this study shows that Celecoxib reduces the DNA repair capacity of MGMT in medulloblastoma and increases the susceptibility to temozolomide. These findings support the use of pharmacological MGMT depletion as a rational approach for intensification of temozolomide therapy in the treatment of medulloblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4354.