Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells.

Abstract

Kinesin spindle protein (KSP), a microtubule-associated motor protein essential for cell cycle progression, is overexpressed in many cancers and is a potential anti-tumor target. We found that inhibition of KSP by a selective inhibitor, ARRY-520, blocked cell cycle progression, leading to apoptosis in acute myeloid leukemia cell lines that express high levels of KSP. Knockdown of p53, overexpression of XIAP and mutation in caspase-8 did not significantly affect sensitivity to ARRY-520, suggesting that the response is independent of p53, XIAP and the extrinsic apoptotic pathway. Although ARRY-520 induced mitotic arrest in both HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, cell death was blunted in HL-60Bcl-2 cells, suggesting that the apoptotic program is executed through the mitochondrial pathway. Accordingly, inhibition of Bcl-2 by ABT-737 was synergistic with ARRY-520 in HL-60Bcl-2 cells. Furthermore, ARRY-520 increased Bim protein levels prior to caspase activation in HL-60 cells. ARRY-520 significantly inhibited tumor growth of xenografts in SCID mice and inhibited AML blast but not normal colony formation, supporting a critical role for KSP in proliferation of leukemic progenitor cells. These results demonstrate that ARRY-520 potently induces cell cycle block and subsequent death in leukemic cells via the mitochondrial pathway and has the potential to eradicate AML progenitor cells.

• Authors: B Z Carter, D H Mak, R Woessner, S Gross, W D Schober, Z Estrov, H Kantarjian, M Andreeff
• Journal: Leukemia (Leukemia) Vol. 23 Issue 10 Pg. 1755-62 (Oct 2009) ISSN: 1476-5551 [Electronic] England
• PMID: 19458629 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• KIF11 protein, human
• Proto-Oncogene Proteins c-bcl-2
• Thiadiazoles
• Tumor Suppressor Protein p53
• X-Linked Inhibitor of Apoptosis Protein
• filanesib
• Caspase 8
• Kinesins

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Caspase 8 (genetics, metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Colony-Forming Units Assay
• Female
• Humans
• Kinesins (antagonists & inhibitors, metabolism)
• Mice
• Mice, SCID
• Mitochondria (drug effects, metabolism)
• Mutation (genetics)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Thiadiazoles (pharmacology)
• Tumor Suppressor Protein p53 (antagonists & inhibitors, metabolism)
• X-Linked Inhibitor of Apoptosis Protein (metabolism)
• Xenograft Model Antitumor Assays