Arenobufagin increases the sensitivity of gastric cancer to cisplatin via alkaliptosis

BACKGROUND: Gastric cancer is the third leading cause of cancer-related death worldwide, for which several novel therapeutic strategies have been developed. Cisplatin (CDDP) mainly exerts its anti-gastric cancer effects; however, drug resistance limits its use. Thus, the development of drugs that can augment their antitumor effects is necessary. Arenobufagin (ArBu) is a novel anticancer drug, and the effects of ArBu in combination with CDDP on gastric cancer have not yet been studied. AIMS: To identify a possible synergistic effect between ArBu and CDDP in gastric cancer and investigate the underlying mechanism. METHODS: Cell viability, colony formation, migration, apoptosis, cell cycle, western blotting, immunofluorescence, and reverse-transcription polymerase chain reaction (RT-PCR) were analyzed in vitro. Western blotting, RT-PCR, hematoxylin and eosin (H&E) staining and blood biochemistry were carried out to examine in vivo. RESULTS: We found that ArBu, in combination with CDDP, effectively inhibited the proliferation and migration of gastric cancer cells, promoted apoptosis, and downregulated the expression of carbonic anhydrase 9 (CA9), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9). In addition, treatment with ArBu in combination with CDDP increased the level of inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB), E-cadherin, and nuclear factor kappa-B/p65 (NF-κB/p65). Furthermore, the combination of ArBu and CDDP inhibited tumor growth in xenograft nude mice with no obvious side effects. CONCLUSIONS: ArBu synergizes with CDDP to inhibit tumor growth both in vivo and in vitro by inducing alkaliptosis. This indicated that ArBu combined with CDDP may serve as a potential agent for the treatment of gastric cancer.