KSP inhibitor SB743921 induces death of multiple myeloma cells via inhibition of the NF-κB signaling pathway

• Published in: BMB reports Vol. 48; no. 10; pp. 571 - 576
• Main Authors: Song, In-Sung, Jeong, Yu Jeong, Nyamaa, Bayalagmaa, Jeong, Seung Hun, Kim, Hyoung Kyu, Kim, Nari, Ko, Kyung Soo, Rhee, Byoung Doo, Han, Jin
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Society for Biochemistry and Molecular Biology 01.10.2015; 생화학분자생물학회
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Benzamides - administration & dosage; Benzamides - pharmacology; Bortezomib - administration & dosage; Bortezomib - pharmacology; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Chromones - administration & dosage; Chromones - pharmacology; Drug Resistance, Neoplasm; Drug Synergism; Humans; Kinesin - antagonists & inhibitors; Kinesin - metabolism; Mitochondria - metabolism; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Signal Transduction - drug effects; 화학
• ISSN: 1976-6696; 1976-670X
• DOI: 10.5483/BMBRep.2015.48.10.015

SB743921 is a potent inhibitor of the spindle protein kinesin and is being investigated in ongoing clinical trials for the treatment of myeloma. However, little is known about the molecular events underlying the induction of cell death in multiple myeloma (MM) by SB743921, alone or in combination treatment. Here, 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. We also found that combination treatment with SB743921 and bortezomib induces death in bortezomib-resistant KMS20 cells. Altogether, 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.