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Objective: To explore the role and mechanism of HM910 in cell proliferation on multiple myeloma.Methods: Human multiple myeloma cell lines RPMI-8226, OPM-2, NCI-H929 and U266 were used to perform an MTT assay for cell viability and the effect of anti-MM proliferation was examined using a human multiple myeloma xenograft model established by NCI-H929 cell in BALB/c-nu mice.Flow cytometry was analyzed for cell apoptosis and cell cycle.Protein turn-over assay was detected for protein degradation.PCR was analyzed for CDK4 mRNA level.Mitochondrial membrane potential (△Ψm) was detected by retention ofrhodamine123.DCFH-DA for reactive oxygen species (ROS) was determined by flow cytometry.Western blotting was performed for the expression of proteins related to cell cycle arrest and apoptosis signaling pathways mediated by HM910.Results: Our results revealed that HM910 effectively inhibited tumor growth in a NCI-H929 xenograft model in vivo.HM910 showed a large effect on anti-MM NCI-H929 cell proliferation was triggering G1 phase arrest with deregulating cell cycle dependent kinase (CDK) 2, CDK4 and CDK6.Additionally, HM910 also suppressed the expression of C-myc and CyclinD1.Importantly, reduced CDK4 by HM910 depended on protein degradation not mRNA level.Further, HM910 could induce MM cell apoptosis via mitochondrial pathway, including reducing mitochondrial transmembrane potential, increase of reactive oxygen species (ROS),activation of caspase3, caspase7, caspase9 as well as poly ADP-ribose polymerase cleavage and mediating the expression of Bcl-2 subfamilies in a concentration-dependent manner.Conclusions: Our data indicated that HM910 suppresses MM cell by halting MM cell cycle progression from G1 to S phase through reducing CDK4 expression.Reduced CDK4 was dependent on protein degradation not mRNA level.Whats more,HM910 could induce apoptosis in MM cells via mitochondrial pathway.Taken together, HM910 may be a viable drug candidate in anti-tumor targeted therapies for human MM.