An Original Aspirin-Containing Carbonic Anhydrase 9 Inhibitor Overcomes Hypoxia-Induced Drug Resistance to Enhance the Efficacy of Myocardial Protection.

Abstract

Hypoxic microenvironment plays a vital role in myocardial ischemia injury, generally leading to the resistance of chemotherapeutic drugs. This induces an intriguing study on mechanism exploration and prodrug design to overcome the hypoxia-induced drug resistance. In this study, we hypothesized that the overexpression of carbonic anhydrase 9 (CAIX) in myocardial cells is closely related to the drug resistance. Herein, bioinformatics analysis, gene knockdown, and overexpression assay certificated the correlation between CAIX overexpression and hypoxia. An original aspirin-containing CAIX inhibitor AcAs has been developed. Based on the downregulation of CAIX level, both in vitro and in vivo, AcAs can overcome the acquired resistance and more effectively attenuate myocardial ischemia and hypoxia injury than that of aspirin. CAIX inhibitor is believed to recover the extracellular pH value so as to ensure the stable effect of aspirin. Results indicate great potential of CAIX inhibitor for further application in myocardial hypoxia injury therapy.