Olaparib Synergizes the Anticancer Activity of Daunorubicin via Interaction with AKR1C3

SAMPLE SUMMARY: Anthracyclines (ANT) are anti-tumor agents frequently used for the treatment of various cancers. Unfortunately, their clinical success is overshadowed by the emergence of drug resistance. Metabolism by carbonyl reducing enzymes (CREs) represents a critical mechanism of ANT resistance. Here, we have explored possible interactions of CREs with olaparib, an FDA-approved targeted chemotherapeutic. Although olaparib has been demonstrated to potentiate the antiproliferative effect of ANT in experimental models, the causing mechanisms remain unclear. In our study, we demonstrated that olaparib potently inhibits the AKR1C3 reductase at clinically relevant concentrations. Furthermore, we showed that this interaction mediates the reversal of ANT resistance and thus represents a critical mechanism of the synergy between ANT and olaparib. Our observations represent valuable knowledge that could be transformed into the more effective therapy of AKR1C3-expressing tumors. ABSTRACT: Olaparib is a potent poly (ADP-ribose) polymerase inhibitor currently used in targeted therapy for treating cancer cells with BRCA mutations. Here we investigate the possible interference of olaparib with daunorubicin (Daun) metabolism, mediated by carbonyl-reducing enzymes (CREs), which play a significant role in the resistance of cancer cells to anthracyclines. Incubation experiments with the most active recombinant CREs showed that olaparib is a potent inhibitor of the aldo–keto reductase 1C3 (AKR1C3) enzyme. Subsequent inhibitory assays in the AKR1C3-overexpressing cellular model transfected human colorectal carcinoma HCT116 cells, demonstrating that olaparib significantly inhibits AKR1C3 at the intracellular level. Consequently, molecular docking studies have supported these findings and identified the possible molecular background of the interaction. Drug combination experiments in HCT116, human liver carcinoma HepG2, and leukemic KG1α cell lines showed that this observed interaction can be exploited for the synergistic enhancement of Daun’s antiproliferative effect. Finally, we showed that olaparib had no significant effect on the mRNA expression of AKR1C3 in HepG2 and KG1α cells. In conclusion, our data demonstrate that olaparib interferes with anthracycline metabolism, and suggest that this phenomenon might be utilized for combating anthracycline resistance.