AKR1B10 and CBR1 inhibitors to improve the efficacy of anthracyclines in cancer treatment

Resistance to chemotherapy is one of the most widespread obstacles to cancer treatment, resulting in a loss of efficacy of cytotoxic agents that consequently leads to prolonged exposure without any therapeutic benefit. Anthracyclines, mainly represented by doxorubicin and daunorubicin (DNB), are natural compounds which find application in cancer treatment; their therapeutical action can be reduced by several cytosolic detoxifying enzymes, such as the Aldo-keto reductase family 1 B 10 member (AKR1B10) and Carbonyl Reductase 1 (CBR1). These enzymes can reduce the C13-carbonyl group of anthracyclines, leading to the formation of alcoholic metabolites, that not only show a reduced antitumoral activity, but are also associated with strong cardiotoxicity. Consequently, the inhibition of these enzymes could increase the efficacy of anthracyclines, improving their antitumoral potential and reducing side effects. A series of thiazolidinone derivatives were tested in vitro for their capacity to act as inhibitors of human recombinant AKR1B10 and/or CBR1. The A549 cells, a human non-small cell lung adenocarcinoma cell line overexpressing both AKR1B10 and CBR1, were also used to evaluate the efficacy of selected compounds. Among tested compounds we identified molecules able to in vitro inhibit at different extent and with different selectivity the two enzymatic targets. Most promising compounds resulted also able to potentiate the cytotoxic effect of DNB in cultured A549 cells. Our results strongly support a relevant involvement of AKR1B10 and CBR1 in detoxification and DNB resistance in the A549 cells model, making the two enzymes relevant targets to reduce anthracyclines chemoresistance.