Synthetic lethality of the ALDH3A1 inhibitor dyclonine and xCT inhibitors in glutathione deficiency-resistant cancer cells

// Shogo Okazaki 1, * , Subaru Shintani 1, * , Yuki Hirata 1 , Kentaro Suina 1 , Takashi Semba 1 , Juntaro Yamasaki 1 , Kiyoko Umene 1 , Miyuki Ishikawa 1 , Hideyuki Saya 1 and Osamu Nagano 1 1 Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan * These authors contributed equally to this work Correspondence to: Osamu Nagano, email: osmna@sb3.so-net.ne.jp Keywords: xCT; ferroptosis, aldehyde dehydrogenase (ALDH); drug repurposing Received: June 21, 2018      Accepted: September 01, 2018      Published: September 18, 2018 ABSTRACT The cystine-glutamate antiporter subunit xCT suppresses iron-dependent oxidative cell death (ferroptosis) and is therefore a promising target for cancer treatment. Given that cancer cells often show resistance to xCT inhibition resulting in glutathione (GSH) deficiency, however, we here 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. This screen identified the oral anesthetic dyclonine which has been recently reported to act as a covalent inhibitor for aldehyde dehydrogenases (ALDHs). Treatment with dyclonine induced intracellular accumulation of the toxic aldehyde 4-hydroxynonenal in a cooperative manner with sulfasalazine. Sulfasalazine-resistant head and neck squamous cell carcinoma (HNSCC) cells were found to highly express ALDH3A1 and knockdown of ALDH3A1 rendered these cells sensitive to sulfasalazine. The combination of dyclonine and sulfasalazine cooperatively suppressed the growth of highly ALDH3A1-expressing HNSCC or gastric tumors that were resistant to sulfasalazine monotherapy. Our findings establish a rationale for application of dyclonine as a sensitizer to xCT-targeted cancer therapy.