Double-acting anticancer drugs to overcome the acquired resistance of malignant cells to chemotherapy

Abstract

Molecular mechanisms underlying the unique ability of angucycline antibiotics of the landomycin family to overcome the acquired multi-drug resistance of tumor cells are studied. This phenomenon is shown to be based on the early induction of hydrogen peroxide in malignant cells without the involvement of mitochondria and the specific binding of these antibiotics to cellular thiols. It is demonstrated that early H2O2 generation by landomycins is mediated by NQO1 enzyme, and the use of its specific inhibitor (dicoumarol) significantly decreased both ROS production and cytotoxic activity of landomycins. Another mode of action of these anticancer antibiotics is tightly connected with their innate ability to bind to cellular thiols, thus leading to depletion of glutathione pool and subsequent induction of apoptosis. Cancer drug resistance is usually associated with increased cellular levels of glutathione, thus the increased affinity of landomycins for thiols may explain the selectivity of their action on drug-resistant tumor cells.