Abstact

CRM1 (Chromosome Region Maintenance 1, also known as Exportin-1 or XPO1) is a key nuclear export factor that exports and inactivates tumor suppressor proteins in cancer. Here, we report that the proton pump inhibitor lansoprazole, upon acid activation, is converted into a CRM1 inhibitor in vitro. The active component is a positively charged molecule that binds noncovalently to the nuclear export signal (NES) groove of CRM1, as revealed by biochemical studies and a 2.0 A cocrystal structure. Interestingly, lansoprazole undergoes spontaneous activation in cells, thereby inhibiting nuclear export to a similar extent as its preacid-activated form. Since the compound is susceptible to inhibition by glutathione (GSH), we designed a combination strategy where cisplatin, by depleting GSH, synergistically enhanced CRM1 inhibition. This combination demonstrated antitumor synergy in a gastric cancer xenograft model without increasing toxicity. Our work presents a novel CRM1 inhibitor and a chemosensitization strategy for gastric cancer.