Abstract C170: The combination of statins and dipyridamole is effective preclinically in AML, MM, and breast cancer.

Abstract

Abstract Statins are drugs that have been utilized for years to treat hyperlipidemia through inhibition of the rate-limiting enzyme of the mevalonate (MVA) pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Preclinical evidence has demonstrated statins to possess anti-cancer properties against a wide range of tumors but not normal cells. Through the use of a chemical library screen, we hypothesize that the identification of compounds which potentiate the anti-cancer effects of statins will uncover novel molecular pathways and/or targets that can be exploited in combination with the MVA pathway to maximize tumor cell death. A pilot 100-compound library, composed of off-patent pharmacologically active drugs clinically used for a wide spectrum of diseases was screened in the multiple myeloma (MM) KMS11 cell line. Dipyridamole (DP), a commonly prescribed anti-platelet agent potentiated the anti-cancer effects of atorvastatin. The DP-statin combination was synergistic and capable of inducing apoptosis in a variety of acute myelogenous leukemia (AML), MM and breast cancer cell lines. The DP-statin combination also induced apoptosis in primary AML patient samples, but was not toxic to normal PBSCs. In an in vivo AML tumor model, the DP-statin combination was found to be effective at inhibiting tumor growth. DP is known to elicit numerous effects, amongst them, phosphodiesterase (PDE) inhibition. In AML cell lines, activators of the PKA pathway including other PDE inhibitors, also induced apoptosis in combination with statins similar to DP. Interestingly, the DP-statin combination prevented the increase of HMGCR, which occurs following statin treatment as part of a classic feedback response. Further mechanistic investigations to determine how DP potentiates statin-induced apoptosis are underway. As both statins and DP are pre-approved for use in humans, off-patent, and readily available, they have the potential to directly impact patient care. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C170.