Kinesin spindle protein inhibitor SB743921 induces mitotic arrest and apoptosis and overcomes imatinib resistance of chronic myeloid leukemia cells.

Abstract

Inhibition of the cell mitotic pathway may provide a novel means for therapeutic intervention in chronic myeloid leukemia (CML). Kinesin spindle protein (KSP), a microtubule-associated motor protein which is essential for cell cycle progression, is overexpressed in bcr-abl+ CML cells. Retrovirus mediated bcr-abl transduction increases KSP expression in cord blood CD34 + cells. SB743921 is a selective KSP inhibitor which is being investigated in ongoing clinical trials for treatment of myeloma, leukemia and solid tumors. Treatment of CML cells with SB743921 resulted in reduced proliferation and colony forming cell (CFC) formation ability. SB743921 also actively blocked cell cycle progression, leading to apoptosis in both primary CML cells and cell lines. KSP inhibition sensitized CML cells to imatinib-induced apoptosis. Importantly, SB743921 inhibited the proliferation of various CML cells including T315I mutation-harboring cells. Furthermore, we demonstrated that SB743921 treatment suppressed ERK and AKT activity in CML cells. These data indicate that SB743921 may become a novel treatment agent for patients with CML.

• Authors: Yue Yin, Huiyan Sun, Jun Xu, Fengjun Xiao, Hua Wang, Yuefeng Yang, Hanyun Ren, Chu-Tse Wu, Chunji Gao, Lisheng Wang
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 56 Issue 6 Pg. 1813-20 (Jun 2015) ISSN: 1029-2403 [Electronic] United States
• PMID: 25146433 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Chromones
• KIF11 protein, human
• SB 743921
• Imatinib Mesylate
• Fusion Proteins, bcr-abl
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Kinesins

Topics

• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Blotting, Western
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cells, Cultured
• Chromones (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fusion Proteins, bcr-abl (genetics)
• Humans
• Imatinib Mesylate (pharmacology)
• K562 Cells
• Kinesins (antagonists & inhibitors, genetics, metabolism)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, pathology)
• Mitosis (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Tumor Cells, Cultured