Abstract 2019: Drug repositioning to induce the synthetic lethality in cancer cells with GSH-depleting therapy

Abstract

Abstract The major cellular antioxidant glutathione (GSH) protects cancer cells from oxidative damage that can lead to the induction of ferroptosis. Inhibitor of the GSH synthesis including buthionine sulfoximine (BSO) and cystine-glutamate antiporter subunit xCT, which mediates the uptake of extracellular cystine and thereby promotes GSH synthesis, thus potential anticancer agents. However, the efficacy of xCT or GSH synthesis-targeted therapy has been found to be diminished by metabolic reprogramming that affects redox status in cancer cells. In this study, we performed a synthetic lethal screen of a drug library to identify agents that sensitize the GSH deficiency-resistant cancer cells to the xCT inhibitor sulfasalazine (SSZ). This screen identified the oral anesthetic dyclonine (DYC) which act as a covalent inhibitor for aldehyde dehydrogenases (ALDHs). Treatment with DYC induced intracellular accumulation of the toxic aldehyde 4-hydroxynonenal (4-HNE) in a cooperative manner with SSZ. The combination of DYC and SSZ cooperatively suppressed the growth of SSZ-resistant tumors. Furthermore, we recently found that a vasodilator oxyfedrine (OXY) also possess the similar structure with dyclonine and induce cell death in BSO-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. Moreover, 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. Citation Format: Yuji Otsuki, Osamu Nagano, Hideyuki Saya. Drug repositioning to induce the synthetic lethality in cancer cells with GSH-depleting therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2019.