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

• 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
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2007.11.007

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.