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영어

Background: Multiple myeloma (MM) is the second most prevalent hematologic malignancy and it is uniformly fatal. Although survival rate has been increased over the last few decades, MM remains as a largely incurable disease with mortality rate. A second generation of kinesin spindle protein (KSP) inhibitor is a new anti-cancer treatment and its targets the mitotic motor kinesin. Methods: MM cell line-KMS20 exhibited cell death, cell cycle arrest and mitochondrial Ca2+ concentrations, mitochondrial ROS level, mitochondrial membrane potential (ψΔm), oxygen consumption and ATP production, under non-treated and SB743921 treated conditions. Results: we report that SB743921 induces mitochondria-mediated cell death via inhibition of the NF-κB signaling pathway, but does not cause cell cycle arrest in KMS20 MM cells. SB743921-mediated inhibition of the NF-κB pathway results in reduced expression of SOD2 and Mcl-1, leading to mitochondrial dysfunction. Moreover, we found that combination treatment with SB743921 and bortezomib induces death in bortezomib- resistant KMS20 cells. Conclusion: Taken together, these data suggest that treatment with SB743921 alone or in combination with bortezomib offers excellent translational potential and promises to be a novel MM therapy.