Improving Anthracycline Therapy Through Carbonyl Reductase Inhibition

Human Carbonyl Reductase (HCBR) is an enzyme responsible for converting a chemotherapeutic class of drugs known as anthracyclines into cardiotoxic metabolites while simultaneously reducing their chemotherapeutic efficacy. My research goal is to identify inhibitors of HCBR that may be of pharmacologic value by maintaining the chemotherapeutic properties of these drugs while reducing their cardiotoxicity; outcomes that may lead to dosage reductions during chemotherapy. The methodology involves evaluating chemical compounds for HCBR inhibition potential using a standard assay containing Menadione, NADPH, and HCBR in a phosphate buffer. All test experiments use UV spectrophotometry to determine reaction activity compared against controls. One HCBR inhibitor was identified which initially appeared promising particularly because of its appealing molecular structure that suggested it may be well received in humans. Subsequent IC-50 studies to determine effective inhibitory concentrations revealed questionable pharmacologic value. My research will continue to test other chemical compounds for possible HCBR inhibition. My research endeavors have provided a wonderful outlet for my curiosity and have helped solidify my understanding of bench research and its contribution in the learning process of disease and biological systems. (NIH Grant # P20 RR016454