Abstract
Abstract The Cox-2 inhibitor Celecoxib has been reported to possess chemopreventive and chemotherapeutic properties, specifically in hormonally-regulated tumors. OSU-03012 is a novel celecoxib derivative, with no COX-2 inhibitory activity, but an order of magnitude greater cell killing ability. We here show that this novel compound has a greater cytotoxicity against a model of anoikis-resistant (AnR) breast cancer. In parallel, anoikis resistance reduces AnR cell sensitivity to the ErbB1/2 dual inhibitor Lapatinib (GW572016, Tykerb, GSK). The two compounds synergize in parental breast cancer cells. Cell killing is achieved partially via induction of ER stress, as measured by eIF2-alpha phosphorylation. We have found that lapatinib resistance may be induced by the aberrant splicing of BCL-X, and that the sensitivity to OSU-03012 is likely due to PTEN dysregulation. In conclusion, these data identify a molecule that may be more efficacious against metastatic tumors, and partially defined its mechanism of action. 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 2081. doi:1538-7445.AM2012-2081
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