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Bayalagmaa Nyamaa,In-Sung Song,Yu Jeong Jeong,Seung Hun Jeong,Hyoung Kyu Kim,Nari Kim,Kyung Soo Ko,Byoung Doo Rhee,Jin Han 동중앙아시아경상학회 2015 한몽경상학회 학술대회 Vol.2015 No.04
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.
( In Sung Song ),( Yu Jeong Jeong ),( Bayalagmaa Nyamaa ),( Seung Hun Jeong ),( Hyoung Kyu Kim ),( Nari Kim ),( Kyung Soo Ko ),( Byoung Doo Rhee ),( Jin Han ) 생화학분자생물학회(구 한국생화학분자생물학회) 2015 BMB Reports Vol.48 No.10
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. [BMB Reports 2015; 48(10): 571-576]
Vu, Thi Thu,Kim, Hyoung Kyu,Le, Thanh Long,Nyamaa, Bayalagmaa,Song, In-Sung,To, Thanh Thuy,Nguyen, Quang Huy,Marquez, Jubert,Kim, Soon Ha,Kim, Nari,Ko, Kyung Soo,Rhee, Byoung Doo,Han, Jin The Korean Society of Pharmacology 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.2
Although the antioxidant and cardioprotective effects of NecroX-5 on various in vitro and in vivo models have been demonstrated, the action of this compound on the mitochondrial oxidative phosphorylation system remains unclear. Here we verify the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity during hypoxia-reoxygenation (HR). Necrox-5 treatment ($10{\mu}M$) and non-treatment were employed on isolated rat hearts during hypoxia/reoxygenation treatment using an ex vivo Langendorff system. Proteomic analysis was performed using liquid chromatography-mass spectrometry (LC-MS) and non-labeling peptide count protein quantification. Real-time PCR, western blot, citrate synthases and mitochondrial complex activity assays were then performed to assess heart function. Treatment with NecroX-5 during hypoxia significantly preserved electron transport chain proteins involved in oxidative phosphorylation and metabolic functions. NecroX-5 also improved mitochondrial complex I, II, and V function. Additionally, markedly higher peroxisome proliferator-activated receptor-gamma coactivator-$1{\alpha}$ ($PGC1{\alpha}$) expression levels were observed in NecroX-5-treated rat hearts. These novel results provide convincing evidence for the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity and in preserving $PGC1{\alpha}$ during cardiac HR injuries.