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.
Highlights
Cancer is one of the most significant health problems worldwide, with 10 million new cases each year [1]
We investigated the potential of 10 and 50 μM olaparib to inhibit selected anthracycline reductases extensively involved in daunorubicin metabolism [9,33]
Considering that olaparib did not display significant inhibition of other anthracyclines reductases, only interactions with aldo–keto reductase 1C3 (AKR1C3) were further investigated at the cellular level
Summary
Cancer is one of the most significant health problems worldwide, with 10 million new cases each year [1]. Over the past 60 years, anthracycline family (ANT) drugs have been commonly used to treat various cancers [2]. These chemotherapeutics effectively induce DNA double-strand breaks in rapidly dividing cells. Despite their efficacy, the application of anthracyclines is limited by dose-limiting toxicity to healthy tissues, as well as drug resistance [3]. Diverse mechanisms may mediate ANT resistance, which may include topoisomerase II mutation [4], cancer stemness, DNA repair, overexpression of P-glycoprotein or other efflux pumps, and metabolism [5]
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