Browse > Article
http://dx.doi.org/10.5483/BMBRep.2015.48.10.015

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

Song, In-Sung (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University)
Jeong, Yu Jeong (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University)
Nyamaa, Bayalagmaa (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University)
Jeong, Seung Hun (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University)
Kim, Hyoung Kyu (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University)
Kim, Nari (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University)
Ko, Kyung Soo (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University)
Rhee, Byoung Doo (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University)
Han, Jin (National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University)
Publication Information
BMB Reports / v.48, no.10, 2015 , pp. 571-576 More about this Journal
Abstract
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 $NF-{\kappa}B$ signaling pathway, but does not cause cell cycle arrest in KMS20 MM cells. SB743921-mediated inhibition of the $NF-{\kappa}B$ 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.
Keywords
SB743921; $NF-{\kappa}B$; multiple myeloma; combination therapy; superoxide dismutase 2; Mcl-1;
Citations & Related Records
Times Cited By KSCI : 4  (Citation Analysis)
연도 인용수 순위
1 Lonial S, Waller EK, Richardson PG et al (2005) Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 106, 3777-3784   DOI
2 Song IS, Jeong YJ, Jeong SH et al (2013) Combination treatment with 2-methoxyestradiol overcomes bortezomib resistance of multiple myeloma cells. Exp Mol Med 45, e50   DOI
3 Kong PJ, Byun JS, Lim SY et al (2008) Melatonin Induces Akt Phosphorylation through Melatonin Receptor- and PI3K-Dependent Pathways in Primary Astrocytes. Korean J Physiol Pharmacol 12, 37-41   DOI
4 Xie H, Hu J, Pan H, Lou Y, Lv P, Chen Y (2014) Adenovirus vector-mediated FAM176A overexpression induces cell death in human H1299 non-small cell lung cancer cells. BMB Rep 47, 104-109   DOI
5 Liu SJ, Yin CX, Ding MC, Xia SY, Shen QM, Wu JD (2014) Berberine suppresses in vitro migration of human aortic smooth muscle cells through the inhibitions of MMP-2/9, u-PA, AP-1, and NF-κB. BMB Rep 47, 388-392   DOI
6 Tan G, Heqing L, Jiangbo C et al (2002) Apoptosis induced by low-dose paclitaxel is associated with p53 upregulation in nasopharyngeal carcinoma cells. Int J Cancer 97, 168-172   DOI
7 Esteve MA, Carre M and Braguer D (2007) Microtubules in apoptosis induction: are they necessary? Curr Cancer Drug Targets 7, 713-729   DOI
8 Staudt LM (2010) Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol 2, a000109   DOI
9 DiDonato JA, Mercurio F and Karin M (2012) NF-kappaB and the link between inflammation and cancer. Immunol Rev 246, 379-400   DOI
10 Song IS, Kim HK, Lee SR et al (2013) Mitochondrial modulation decreases the bortezomib-resistance in multiple myeloma cells. Int J Cancer 133, 1357-1368   DOI
11 Park J, Bae EK, Lee C et al (2014) Establishment and characterization of bortezomib-resistant U266 cell line: constitutive activation of NF-kappaB-mediated cell signals and/or alterations of ubiquitylation-related genes reduce bortezomib-induced apoptosis. BMB Rep 47, 274-279   DOI
12 Yi MJ, Park SH, Cho HN et al (2002) Heat-shock protein 25 (Hspb1) regulates manganese superoxide dismutase through activation of Nfkb (NF-kappaB). Radiat Res 158, 641-649   DOI
13 Lam LT, Davis RE, Pierce J et al (2005) Small molecule inhibitors of IkappaB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling. Clin Cancer Res 11, 28-40   DOI
14 Richardson PG, Hideshima T, Mitsiades C and Anderson KC (2007) The emerging role of novel therapies for the treatment of relapsed myeloma. J Natl Compr Canc Netw 5, 149-162
15 San Miguel J, Blade J, Boccadoro M et al (2006) A practical update on the use of bortezomib in the management of multiple myeloma. Oncologist 11, 51-61   DOI
16 Chauhan D, Li G, Podar K et al (2004) Targeting mitochondria to overcome conventional and bortezomib/ proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells. Blood 104, 2458-2466   DOI
17 Ocio EM, Mateos MV, Maiso P, Pandiella A and San- Miguel JF (2008) New drugs in multiple myeloma: mechanisms of action and phase I/II clinical findings. Lancet Oncol 9, 1157-1165   DOI
18 Enos AP and Morris NR (1990) Mutation of a gene that encodes a kinesin-like protein blocks nuclear division in A. nidulans. Cell 60, 1019-1027   DOI
19 Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100, 57-70   DOI
20 Vale RD and Fletterick RJ (1997) The design plan of kinesin motors. Annu Rev Cell Dev Biol 13, 745-777   DOI
21 Sawin KE and Mitchison TJ (1995) Mutations in the kinesin-like protein Eg5 disrupting localization to the mitotic spindle. Proc Natl Acad Sci U S A 92, 4289-4293   DOI
22 Rowinsky EK, Chaudhry V, Cornblath DR and Donehower RC (1993) Neurotoxicity of Taxol. J Natl Cancer Inst Monogr, 107-115
23 Talapatra SK, Anthony NG, Mackay SP and Kozielski F (2013) Mitotic kinesin Eg5 overcomes inhibition to the phase I/II clinical candidate SB743921 by an allosteric resistance mechanism. J Med Chem 56, 6317-6329   DOI
24 Yin Y, Sun H, Xu J et al (2014) Kinesin spindle protein inhibitor SB743921 induces mitotic arrest and apoptosis and overcomes imatinib resistance of chronic myeloid leukemia cells. Leuk Lymphoma, 1-8
25 Kyle RA and Rajkumar SV (2004) Multiple myeloma. N Engl J Med 351, 1860-1873   DOI