37th World Congress on Pharmacology
Amsterdam, Netherlands
Gang-Min Hur
Chungnam National University, South Korea
Title: Rubianol B isolated from Rubia philippinesis induces RIP1/RIPK3-dependentg necroptosis in human colorectal cancer cells
Biography
Biography: Gang-Min Hur
Abstract
Receptor interacting protein 1 (RIP1) has emerged as a key molecular switch in inducing necroptosis, an alternative programmed cell death mode that can overcome apoptosis resistance in cancer therapy. Therefore, discovering a substance that modulates the cytotoxic potential of RIP1 may provide an effective strategy to bypass apoptosis resistance in cancer chemotherapeutics. In this study, it was found that rubianol-B, a triterpenoids purified from Rubia phillippinesis, promoted RIP1-dependent apoptosis via caspase-8 activation in multiple types of human cancer cells. Interestingly, pharmacological or genetic inhibition of caspase-8 was sufficient to switch the cell death mode from apoptosis to necroptosis following rubianol-B treatment, through necrosome formation in RIPK3-expressing human colorectal cancer (CRC) cells, accompanied by the upregulation of cytotoxic potential of RIP1 phosphorylation. Conversely, rubianol-B-induced cell death was almost completely abrogated by RIPK deficiency. The enhanced RIP1 phosphorylation and necroptosis triggered by rubianol-B treatment occurred independently of tumor necrosis factor receptor signaling, and was mediated by the production of reactive oxygen species via NADPH oxidase 1 in CRC cells. Thus, it is proposed that rubianol-B is a novel anticancer agent that enhances the cytotoxic potential of RIP1, warranting further development of rubianol-B as a necroptosis-targeting compound in apoptosis-resistant CRC