The major cellular
antioxidant glutathione (GSH) protects
cancer cells from oxidative damage that can lead to the induction of ferroptosis, an
iron-dependent form of cell death triggered by the aberrant accumulation of
lipid peroxides. Inhibitors of the
cystine-
glutamate antiporter subunit xCT, which mediates the uptake of extracellular
cystine and thereby promotes GSH synthesis, are thus potential
anticancer agents. However, the efficacy of xCT-targeted
therapy has been found to be diminished by metabolic reprogramming that affects redox status in
cancer cells. Identification of drugs for combination with xCT inhibitors that are able to overcome resistance to xCT-targeted
therapy might thus provide the basis for effective
cancer treatment. We have now identified the
vasodilator oxyfedrine (OXY) as a sensitizer of
cancer cells to GSH-depleting agents including the xCT inhibitor
sulfasalazine (SSZ).
Oxyfedrine contains a structural motif required for covalent inhibition of
aldehyde dehydrogenase (ALDH)
enzymes, and combined treatment with OXY and SSZ was found to induce accumulation of the cytotoxic
aldehyde 4-hydroxynonenal and cell death in SSZ-resistant
cancer cells both in vitro and in vivo. Microarray analysis of
tumor xenograft tissue showed
cyclooxygenase-2 expression as a potential
biomarker for the efficacy of such combination
therapy. Furthermore, OXY-mediated ALDH inhibition was found to sensitize
cancer cells to GSH depletion induced by
radiation therapy in vitro. Our findings thus establish a rationale for repurposing of OXY as a sensitizing drug for
cancer treatment with agents that induce GSH depletion.