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

Song, In Sung; Jeong, Yu Jeong; Nyamaa, Bayalagmaa; Jeong, Sang Hoon; Kim, Hyoung Kyu; Kim, Nari; Ko, Kyung Soo; Rhee, Byoung Doo; Han, Jin

doi:10.5483/bmbrep.2015.48.10.015

Cited by 12 publications

(9 citation statements)

References 23 publications

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“…Inhibition of the NFκB signal transduction pathway by the kinesin spindle protein inhibitor SB715992 (1 n M concentration) in human multiple myeloma cells results in reduced SOD2 expression and induces cell death in 24 h (335), therefore confirming the role of NFκB in SOD2 stimulation and suggesting a growth-supportive role for the enzyme. Indeed, overexpression of miR146a downregulated SOD2 , reduced human epithelial ovarian cancer cell proliferation, increased apoptosis, and increased sensitivity to chemotherapy (67).…”

Section: Manganese Sod Mnsod Sod2mentioning

confidence: 78%

Carcinogenesis and Reactive Oxygen Species Signaling: Interaction of the NADPH Oxidase NOX1–5 and Superoxide Dismutase 1–3 Signal Transduction Pathways

Parascandolo

Laukkanen

2019

Antioxidants & Redox Signaling

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Section: Manganese Sod Mnsod Sod2mentioning

confidence: 78%

Carcinogenesis and Reactive Oxygen Species Signaling: Interaction of the NADPH Oxidase NOX1–5 and Superoxide Dismutase 1–3 Signal Transduction Pathways

Parascandolo

Laukkanen

2019

Antioxidants & Redox Signaling

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“…It has been recognized as a valuable drug target for anticancer therapies and several classes of Eg5 inhibitors have been developed 14 . Monastrol, ispinesib and (+)-S-Trityl-L-cysteine (TriC) are the loop-5 inhibitors and can weaken Eg5 binding to MTs, disrupting Eg5dependent outward force production and inducing the formation of monopolar spindles with unseparated spindle poles [14][15][16][17][18][19] . BRD9876 (BRD) is the "rigor" inhibitor that locks Eg5 in a state with enhanced MT binding, leading to bundling and stabilization of MTs 20,21 .…”

Section: Introductionmentioning

confidence: 99%

HSP70 regulates Eg5 distribution within the mitotic spindle and modulates the cytotoxicity of Eg5 inhibitors

et al. 2020

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The heat shock protein 70 (HSP70) is a conserved molecular chaperone and proteostasis regulator that protects cells from pharmacological stress and promotes drug resistance in cancer cells. In this study, we found that HSP70 may promote resistance to anticancer drugs that target the mitotic kinesin, Eg5, which is essential for assembly and maintenance of the mitotic spindle and cell proliferation. Our data show that loss of HSP70 activity enhances Eg5 inhibitor-induced cytotoxicity and spindle abnormalities. Furthermore, HSP70 colocalizes with Eg5 in the mitotic spindle, and inhibition of HSP70 disrupts this colocalization. Inhibition or depletion of HSP70 also causes Eg5 to accumulate at the spindle pole, altering microtubule dynamics and leading to chromosome misalignment. Using ground state depletion microscopy followed by individual molecule return (GSDIM), we found that HSP70 inhibition reduces the size of Eg5 ensembles and prevents their localization to the inter-polar region of the spindle. In addition, bis(maleimido)hexane-mediated protein-protein crosslinking and proximity ligation assays revealed that HSP70 inhibition deregulates the interaction between Eg5 tetramers and TPX2 at the spindle pole, leading to their accumulation in high-molecular-weight complexes. Finally, we showed that the passive substrate-binding activity of HSP70 is required for appropriate Eg5 distribution and function. Together, our results show that HSP70 substratebinding activity may regulate proper assembly of Eg5 ensembles and Eg5-TPX2 complexes to modulate mitotic distribution/function of Eg5. Thus, HSP70 inhibition may sensitize cancer cells to Eg5 inhibitor-induced cytotoxicity.

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“…Previous reports have indicated that SB 743921 has shown a wide range of anticancer activities against a variety of malignancies including cervical carcinoma, lymphoma, multiple myeloma, and myeloid leukemia 13,19,20. In this study, we evaluated the potential antitumor effects of SB743921 on breast cancer cells.…”

Section: Resultsmentioning

confidence: 99%

KSP inhibitor SB743921 inhibits growth and induces apoptosis of breast cancer cells by regulating p53, Bcl-2, and DTL

Zhu

Xiao

et al. 2016

Anti-Cancer Drugs

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Kinesin spindle protein (KSP) is a microtubule-associated motor protein that is specifically expressed by mitosis cells. It is highly expressed in various types of tumors including hematomalignances and solid tumors. Chemical KSP inhibition has become a novel strategy in the development of anticancer drugs. SB743921 is a selective inhibitor for KSP, which is a mitotic protein essential for cell-cycle progression. Although SB743921 has shown antitumor activities for several types of cancers and entered into clinical trials, its therapeutic effects on breast cancer and mechanisms have not been explored. In this study, we tested the antitumor activity of SB743921 in breast cancer cell lines and partly elucidated its mechanisms. KSP and denticleless E3 ubiquitin–protein ligase homolog (DTL) are overexpressed in breast cancer cells compared with no-cancer tissues. Chemical inhibition of KSP by SB743921 not only reduces proliferation but also induces cell-cycle arrest and leads to apoptosis in breast cancer cells. Treatment of MCF-7 and MDA-MB-231 breast cancer cell lines with SB743921 results in decreased ability of colony formation in culture. SB743921 treatment also causes a KSP accumulation in protein level that is associated with cell arrest. Furthermore, we showed that SB743921 treatment significantly reduces the expression of bcl-2 and cell cycle-related protein DTL, and upregulates p53 and caspase-3 in breast cancer cells. Taken together, these data indicated that SB743921 can be expected to be a novel treatment agent for breast cancers.

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

Cited by 12 publications

References 23 publications

Carcinogenesis and Reactive Oxygen Species Signaling: Interaction of the NADPH Oxidase NOX1–5 and Superoxide Dismutase 1–3 Signal Transduction Pathways

Carcinogenesis and Reactive Oxygen Species Signaling: Interaction of the NADPH Oxidase NOX1–5 and Superoxide Dismutase 1–3 Signal Transduction Pathways

HSP70 regulates Eg5 distribution within the mitotic spindle and modulates the cytotoxicity of Eg5 inhibitors

KSP inhibitor SB743921 inhibits growth and induces apoptosis of breast cancer cells by regulating p53, Bcl-2, and DTL

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