Two death pathways induced by sorafenib in myeloma cells: Puma-mediated apoptosis and necroptosis.

摘要: Purpose Sorafenib is a multikinase inhibitor that targets the MAPK pathway and currently used for treatment of hepatocellular renal carcinoma. Recently, it has been shown sorafenib also cytotoxic to multiple myeloma (MM) cells. Here, we have further analyzed mechanism sorafenib-induced death in MM Methods Cell induced by cell lines plasma cells from patients was evaluated analysis gene expression RT-MLPA quantitative PCR, protein levels functionality Western blot flow cytometry silencing with siRNA. Results characterized phosphatidylserine exposure, DWm loss, cytochrome c release caspase activation, hallmarks apoptosis. DL50 at 24 h ranged 6 10 lM. Ex vivo 20 lM apoptosis around 80 % six patients. caspasedependent degradation Bcl-xL Mcl-1 proteins, destabilizing mitochondria speeding up development increased Puma mRNA level siRNA confirmed relevant role induction Co-treatment pan-caspase Z-VAD-fmk prevented variable degree depending on line. In RPMI 8226 cells, most death. However, MM.1S only co-incubation both RIP1K necrostatin-1, indicating under conditions inefficient induces necroptosis. Conclusion Our results demonstrate key triggering this drug can induce necroptosis