Small-molecule inhibition of Aurora kinases triggers spindle checkpoint-independent apoptosis in cancer cells

Aurora kinases are key regulators of mitotic progression and have also been implicated in tumorigenesis. Small molecules that inhibit Aurora kinases have shown impressive anticancer activity in preclinical studies and are currently under clinical evaluation. In this study, our data show that suppres...

Full description

Saved in:
Bibliographic Details
Published in:Biochemical pharmacology 2008-03, Vol.75 (5), p.1027-1034
Main Authors: Sun, Lei, Li, Dengwen, Dong, Xin, Yu, Haiyang, Dong, Jin-Tang, Zhang, Chuanmao, Lu, Xianyu, Zhou, Jun
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Aurora Kinases
Biological and medical sciences
Breast cancer
Calcium-Binding Proteins - genetics
Cell Cycle Proteins - genetics
Cell Line, Tumor
Cell Proliferation - drug effects
Gynecology. Andrology. Obstetrics
Humans
Mad2 Proteins
Mammary gland diseases
Medical sciences
Mitosis
Models, Molecular
Pharmacology. Drug treatments
Protein Kinase Inhibitors - pharmacology
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Quinazolines - pharmacology
Repressor Proteins - genetics
RNA, Small Interfering - genetics
Spindle Apparatus
Spindle checkpoint
Tumors
Vinblastine - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Aurora kinases are key regulators of mitotic progression and have also been implicated in tumorigenesis. Small molecules that inhibit Aurora kinases have shown impressive anticancer activity in preclinical studies and are currently under clinical evaluation. In this study, our data show that suppression of Aurora activity with a specific inhibitor prevents the proliferation of breast cancer cells. Molecular modeling studies indicate that the Aurora inhibitor suppresses Aurora activity by competitive displacement of ATP. Mechanistically, the Aurora inhibitor causes the accumulation of multinucleated cells, leading to profound apoptosis in the absence of caspase-3 activity. Further studies show that the sensitivity of cancer cells to the Aurora inhibitor is independent of the spindle checkpoint. In addition, the Aurora inhibitor acts synergistically with the vinca alkaloids but not with the taxanes in inhibiting cell proliferation and inducing apoptosis. These results suggest that Aurora inhibitors might be effective in spindle checkpoint-defective cancer cells and a combination of Aurora inhibitors with the vinca alkaloids is a promising approach for cancer chemotherapy.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2007.11.007