Olaparib Synergizes the Anticancer Activity of Daunorubicin via Interaction with AKR1C3.

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Tavares TS, Hofman J, Lekesova A, Zelazkova J, Wsol V

Olaparib Synergizes the Anticancer Activity of Daunorubicin via Interaction with AKR1C3.

Cancers (Basel). 2020 Oct 26;12(11). pii: cancers12113127. doi: 10.3390/cancers12113127.

PubMed ID

33114555 [ View in PubMed

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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 KG1alpha 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 KG1alpha cells. In conclusion, our data demonstrate that olaparib interferes with anthracycline metabolism, and suggest that this phenomenon might be utilized for combating anthracycline resistance.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Olaparib	Aldo-keto reductase family 1 member C3	Protein	Humans	Unknown	Inhibitor	Details
Olaparib	Poly [ADP-ribose] polymerase 1	Protein	Humans	Yes	Inhibitor	Details