Arenobufagin increases the sensitivity of gastric cancer to cisplatin via alkaliptosis

Abstract

Abstract Purpose Gastric cancer is the third leading cause of cancer-related deaths worldwide. Few novel therapeutic strategies have been developed for gastric cancer. Cisplatin (CDDP) mainly exerts its anti-gastric cancer effect, but its resistance limits use. Thus, application of drugs which could augment its anti-tumor effect is necessary. Arenobufagin (ArBu) was identified as a novel anti-cancer agent. However, the effect of ArBu combined with CDDP on gastric cancer has not been studied. To identify a possible synergistic effect between ArBu and CDDP on gastric cancer and to investigate the underlying mechanism. Methods The cell viability, colony formation, migration, apoptosis, cell cycle, Western blotting, immunofluorescence and reverse-transcription polymerase chain reaction were analyzed in vitro. Western blotting, reverse-transcription, hematoxylin-eosin staining and blood biochemistry were carried out to examine in vivo. Results We found that ArBu combination with CDDP effectively inhibited the proliferation, migration of gastric cancer cells and promoted apoptosis of cells, downregulation of CA9, matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) expression. In addition, treatment with ArBu combination CDDP increased the level of inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB), E-cadherin and Nuclear factor-k-gene binding (NF-κB). Furthermore, ArBu combination with CDDP also exerted inhibitory effects on tumor growth in xenograft nude mice and no obvious side effects. Conclusion ArBu synergized with CDDP to inhibit tumor growth in vivo and in vitro through induction of alkaliptosis. This indicates that ArBu combination with CDDP may serve as a potential agent for the treatment of gastric cancer.