Akiyama Masaki, Izumi Hiroto, Wang Ke-Yong, Yamaguchi Takahiro, Kuma Akihiro, Kitamura Noriaki, Harada Yoshikazu, Oya Ryoichi, Yamaguchi Koji, Iwai Yoshiko, Kohno Kimitoshi
President Laboratory, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
Anticancer Agents Med Chem. 2014;14(7):1042-50. doi: 10.2174/1871520614666140207154351.
The 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.
极光激酶是丝氨酸/苏氨酸激酶，对有丝分裂至关重要，并与肿瘤发生有关。因此，极光激酶有望用于分子靶向治疗。在本研究中，我们证明极光B激酶（AURKB）在顺铂和奥沙利铂耐药细胞中均过表达。下调AURKB可使细胞对顺铂和奥沙利铂敏感，但对紫杉醇、5-氟尿嘧啶或过氧化氢不敏感。有趣的是，我们发现顺铂和奥沙利铂耐药细胞对AURKB特异性抑制剂AZD1152 HQPA和ZM447439均高度敏感，这表明顺铂和奥沙利铂耐药细胞对AURKB产生了依赖性。这些数据证明极光激酶抑制剂可以克服顺铂和奥沙利铂耐药性。因此，如果在一线铂类化疗后使用，AURKB抑制剂可能会带来潜在益处。
