Toxicology and Applied Pharmacology

Biography

Biography: Eva Novotna

Abstract

Anthracyclines, in particular, doxorubicin (Dox) and daunorubicin (Dau), have been used as a key part of many cancer treatment regimes, but their usefulness is limited by intrinsic and/or acquired resistance. Pharmacokinetic anthracycline resistance is associated with the enzymatic detoxification and with changes in anthracycline absorption and retention. The major anthracycline metabolic pathway in humans is mediated by a group of cytosolic NADPH-dependent carbonyl reducing enzymes from AKR and SDR superfamilies that catalyze two-electron reduction of Dau and Dox to less active metabolites. Cyclin-dependent kinases (CDK) are key regulators of cell cycle progression, and defects in their regulation are associated with many human pathologies. The CDK inhibitors purvalanol A and roscovitine are purine analogs with different potencies and selectivities. Recent studies showed that roscovitine could effectively kill anthracycline-resistant cancer cells and increase the therapeutic activity of anthracyclines. Although beneficial effects of these combinations have been demonstrated, the molecular mechanisms have not been fully understood yet. In our study, we proved that both purvalanol A and roscovitine significantly inhibit recombinant AKR1C3 with IC50 values of 6.6 and 2.2 M, respectively. Kinetic measurements showed that the ARK1C3-mediated reduction of Dau is inhibited in a noncompetitive manner. Both the drugs were also active at the cellular level in the experiments with transiently transfected HCT116 cells. In the follow up combination experiments, we demonstrated that the inhibition of AKR1C3 by roscovitine and purvalanol A has a potential to overcome the Dau resistance mediated by this enzyme. The dose reduction indices suggest a potential of the examined combinations to increase the safety of the treatment with the involved drugs.