Cinnamic acid derivatives as chemosensitising agents against DOX-treated lung cancer cells - Involvement of carbonyl reductase 1

Doxorubicin (DOX) therapy is limited by both cancer cells resistance and cardiotoxicity. DOX biotransformation to doxorubicinol (DOXol) by reductases enzymes (mainly by CBR1; carbonyl reductase 1) is a key process responsible for DOX adverse effects development. Thus, inhibition of CBR1 can increase the therapeutic effect of DOX. In the present study, we used a group of new synthetized cinnamic acid (CA) derivatives to improve the effectiveness and safety profile of DOX therapy against cancer cells in vitro. The possible mechanism of CBR1 inhibition was simulated by molecular modelling studies. The kinetics of DOX reduction in the presence of active CA derivatives were measured in cytosols. The chemosensitising activity of CA derivatives including proapoptotic, anti-invasiveness activity were investigated in A549 lung cancer cell line. In our research 7 from 16 tested CA derivatives binded to the active site of CBR1 enzyme and improved DOX stability by inhibition of DOXol formation. Co-treatment of A549 cells with active CA derivatives and DOX induced cells apoptosis by activation of caspase cascade. At the same time we observed decrease of invasive properties (cell migration and transmigration assays) and the rearangments of F-actin cytoskeleton in CA derivatves + DOX treated cells. Meanwhile, control, human lung fibroblasts stay realtivelly unvulnerable and viable. New synthetized CA derivatives may inhibit the activity of CBR1 leading to the stabilization of DOX therapeutic levels in cancer cells and to protect the myocardium against DOXol cytotoxic effect. Favourable physicochemical properties supported by a safety profile and multidirectional chemosensitising activity render CA derivatives a promising group for the development of agent useful in combined therapy.

Keywords: CBR1; Chemosensitizing; Cinnamic acid derivatives; Doxorubicin; Lung cancer.