UC Santa Cruz

Cancer cells have the ability to develop resistance to traditional therapies, resulting in poor patient outcomes. The increasing prevalence of chemotherapeutic resistant cancers demands novel therapies that address this issue. One intriguing strategy is the recent development of carbon monoxide (CO) as a potential cancer therapeutic. CO is a gasotransmitter, an endogenously produced, diffusible, signaling molecule with essential roles in physiological processes, including resolving inflammation. Cancer, a disease characterized by chronic up-regulation of inflammatory processes, could be an intriguing therapeutic candidate for CO. Preliminary studies have reported CO to be a chemosensitizing agent, but the mechanism(s) by which this effect occurs are largely unknown. If the therapeutic potential of CO is to be realized, understanding of the chemical biology of CO in the cancer cell is essential. Identified here are two targets of CO that mediate sensitization of cancer cells to standard chemotherapeutics, including doxorubicin, paclitaxel and cisplatin: cystathionine β-synthase (CBS) in breast and ovarian cancer cells and cytochrome P450 3A4/2C8 (CYP3A4/2C8) in breast cancer cells. In studying CO-mediated inhibition of these two enzymes, molecular mechanisms of drug resistance, promoted and maintained by the enzymatic actions of CBS and CYP3A4/2C8, were revealed. Additionally, reported here is the synthesis of a novel class of CO-donating molecules, a CO-releasing molecule-conjugated to monoclonal antibodies, capable of delivering therapeutic levels of CO to a cancer target with antigen-specificity. Collectively these results suggest co-administration of CO with existing cancer treatment regimens may ultimately improve clinical outcomes in cancer therapy.