O6 methylguanine DNA methyltransferease (MGMT) is over expressed in breast cancer cells. A number of cytotoxic agents utilized in the treatment of cancer directly or indirectly damage DNA, thus initiating a cascade of events which finalizes in cell death. MGMT has received significant focus for its role in the repair of DNA damage caused by a number of chemotherapeutics including alkylating agents, chlorethylating and methylating agents. In the present study, we tested the administration of the MGMT inhibitor [O6-benzylguanine (BG)] at non-toxic doses in combination with MGMT alkylator (temozolomide) on breast cancer cells in cell culture and xenograft models. Here, we report that temozolomide in combination with BG effectively inhibits breast cancer cell growth in vitro and in vivo. Here, we also report that BG either alone or in combination with temozolomide inhibits gene expressions which are involved in breast tumorigenesis and cell division process (CDC20, TOP2A, AURKB, BIRC5) and induces the expression of p21cip1 cell cycle inhibitor. The combination also enhanced PARP cleavage, indicative of apoptosis. In breast cancer xenograft models, BG alone or in combination with temozolomide caused marked delay in tumor growth. These findings suggest that MGMT inhibition may provide a novel and effective approach for breast cancer growth inhibition. Furthermore, the combination of MGMT inhibitors and MGMT alkylators can provide alternative therapeutic approaches to treat breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3721. doi:1538-7445.AM2012-3721