Abstract 5065: Orally active nontoxic dual MMP2 and CAIX inhibitors as anticancer therapy.

Abstract

Abstract Carbonic anhydrases IX and XII, (CAIX and CAXII) are critical to maintain a low pH in the tumor cell's microenvironment, and MMP-2 is critical for breaching the basement membrane that opens the way to the dissemination of metastases. The expression of carbonic anhydrase IX (CAIX), a marker for hypoxic tumors, is correlated with poor prognosis. In this presentation, we wish to report that carbamoylphosphonates (CPOs) have been identified as orally bioavailable dual inhibitors of matrix metalloproteinase-2 (MMP-2) on the one hand, and carbonic anhydrases (CAs) on the other hand, especially the IX and XII isoforms, well known as cancer promoting factors. We have also demonstrated that the ionized CPO acids are unable to cross the cell membrane and thus are limited to interact with enzymes present in the extracellular domains of as are both CA isozymes CAIX and CAXII and MMP-2. Finally, exposing cancer cells to CPOs in hypoxic conditions resulted in the dose dependent release of lactate dehydrogenase, confirming the direct interaction of the CPOs with the cancer related isozymes CAIX and XII and thereby promoting cellular damage. Thus, CPOs can be regarded as novel orally active nontoxic drug candidates for CAIX expressing tumor targeted chemotherapy acting by two synergistic mechanisms, namely, inhibiting CAs and MMPs simultaneously. Citation Format: Eli Breuer. Orally active nontoxic dual MMP2 and CAIX inhibitors as anticancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5065. doi:10.1158/1538-7445.AM2013-5065