IMB5036 inhibits human pancreatic cancer growth primarily through activating necroptosis

Abstract

IMB5036 is a novel pyridazinone compound with potent cytotoxicity. In this study, we reported its antitumour activity against pancreatic cancer and the underlying mechanism. We found that IMB5036 induced rapid cell swelling and increased membrane permeability in pancreatic cancer cells. IMB5036 increased the ratio of PI+ cells, which could be rescued by necroptosis inhibitor. Furthermore, MLKL inhibitor NSA attenuated the killing effect of IMB5036 on pancreatic cancer cells. IMB5036 stimulated translocation of MLKL and p-MLKL from cytoplasm to cell membrane. IMB5036 upregulated the level of p-RIPK1, p-RIPK3, and p-MLKL. At the same time, IMB5036 also partially activated apoptosis and pyroptosis. IMB5036 inhibited tumour growth in pancreatic xenograft. IMB5036 induced larger necrosis area, increased p-MLKL level, and inhibited Ki67 expression in tumour mass. The study indicates that IMB5036 inhibits human pancreatic cancer growth primarily activating necroptosis.

Keywords: MLKL; cell death; necroptosis; pancreatic cancer; pyridazinone.