Use of Enzymatically Activated Carbon Monoxide Donors for Sensitizing Drug-Resistant Tumor Cells.

The application of gaseous signaling molecules like NO, HS or CO to overcome the multidrug resistance in cancer treatment has proven to be a viable therapeutic strategy. The development of CO-releasing molecules (CORMs) in a controlled manner and in targeted tissues remains a challenge in medicinal chemistry. In this paper, we describe the design, synthesis and chemical and enzymatic stability of a novel non-metal CORM () able to release intracellularly CO and, simultaneously, facilitate fluorescent degradation of products under the action of esterase. The toxicity of against different human cancer cell lines and their drug-resistant counterparts, as well as the putative mechanism of toxicity were investigated. The drug-resistant cancer cell lines efficiently absorbed and was able to restore their sensitivity vs. chemotherapeutic drugs by causing a CO-dependent mitochondrial oxidative stress that culminated in mitochondrial-dependent apoptosis. These results demonstrate the importance of CORMs in cases where conventional chemotherapy fails and thus open the horizons towards new combinatorial strategies to overcome multidrug resistance.