Hypersensitivity to Aurora Kinase Inhibitors in Cells Resistant against Platinum- Containing Anticancer Agents
Anti-Cancer Agents in Medicinal Chemistry,
Masaki Akiyama, Hiroto Izumi, Ke-Yong Wang, Takahiro Yamaguchi, Akihiro Kuma, Noriaki Kitamura, Yoshikazu Harada, Ryoichi Oya, Koji Yamaguchi, Yoshiko Iwai and Kimitoshi KohnoAffiliation:
President Laboratory, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
AbstractThe aurora kinases are serine/threonine kinases that are essential for mitosis and contribute to tumorigenesis. Therefore, aurora kinases hold promise for molecularly targeted therapy. In the present study, we demonstrated that aurora B kinase (AURKB) is overexpressed in both cisplatin- and oxaliplatin-resistant cells. Downregulation of AURKB sensitized cells to both cisplatin and oxaliplatin, but not to paclitaxel, 5-FU or hydrogen peroxide. Interestingly, we found that both cisplatin- and oxaliplatin-resistant cells were hypersensitive to the AURKB specific inhibitors, AZD1152 HQPA and ZM447439, suggesting that both cisplatin- and oxaliplatinresistant cells develop an addiction to AURKB. These data provide evidence that aurora kinase inhibitors can overcome both cisplatin and oxaliplatin resistance. Therefore, AURKB inhibitors could offer potential benefits if used after first-line platinum-based chemotherapy.
Acquired drug resistance, addiction, AURKB, AURKB inhibitor, cisplatin, oxaliplatin.
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