Polo-like Kinase Inhibitor Ro5203280 Has Potent Antitumor Activity in Nasopharyngeal Carcinoma
Polo-like Kinase Inhibitor Ro5203280 Has Potent Antitumor Activity in Nasopharyngeal Carcinoma
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DOI：
10.1158/1535-7163.mct-12-1219
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发表时间：
2013-08-01
影响因子：
5.7
通讯作者：
Lung, Maria Li
中科院分区：
文献类型：
--
作者：
Cheung, Arthur Kwok Leung;Ip, Joseph Chok Yan;Lung, Maria Li
鼻咽癌是中国南方地区发病率最高的癌症，在世界其他地方很少见。主要治疗方式包括化疗和放疗。然而，肿瘤化疗耐药性常常限制鼻咽癌治疗的疗效并降低生存率。因此，需要寻找新的选择性化疗药物来治疗鼻咽癌。在当前的这项研究中，研究了 Polo 样激酶抑制剂 Ro5203280 的抗肿瘤功效。 Ro5203280 在体外和体内均诱导肿瘤抑制。在测试的高度增殖的癌细胞系中观察到抑制作用，但在非致瘤细胞系中没有观察到抑制作用。实时细胞增殖和荧光激活细胞分选 (FACS) 分析，以及免疫组织化学 (IHC)、免疫荧光和膜联蛋白 V 染色测定，用于评估药物治疗对细胞周期和细胞凋亡的影响。 Ro5203280 诱导 G(2)-M 细胞周期停滞和细胞凋亡。蛋白质印迹显示它在体外和体内抑制 PLK1 磷酸化并下调下游信号分子 Cdc25c，并上调两个重要的有丝分裂调节因子 Wee1 和 Securin 以及 DNA 损伤相关因子 Chk2。 Ro5203280静脉注射的体内致瘤性测定显示其具有抑制小鼠肿瘤生长的强大能力，且没有可观察到的毒性迹象。这些发现表明 Ro5203280 作为鼻咽癌化疗靶向药物的潜在用途。 (C)2013 AACR。
Nasopharyngeal carcinoma is a cancer with its highest prevalence among the southern Chinese and is rare elsewhere in the world. The main treatment modalities include chemotherapy and radiotherapy. However, tumor chemoresistance often limits the efficacy of nasopharyngeal carcinoma treatment and reduces survival rates. Thus, identifying new selective chemotherapeutic drugs for nasopharyngeal carcinoma treatment is needed. In this current study, the antitumor efficacy of a polo-like kinase inhibitor, Ro5203280, was investigated. Ro5203280 induces tumor suppression both in vitro and in vivo. An inhibitory effect was observed with the highly proliferating cancer cell lines tested, but not with the nontumorigenic cell line. Real-time cell proliferation and fluorescence-activated cell sorting (FACS) analysis, together with immunohistochemical (IHC), immunofluorescence, and Annexin V staining assays, were used to evaluate the impact of drug treatment on cell cycle and apoptosis. Ro5203280 induces G(2)-M cell-cycle arrest and apoptosis. Western blotting shows it inhibits PLK1 phosphorylation and downregulates the downstream signaling molecule, Cdc25c, and upregulates two important mitosis regulators, Wee1 and Securin, as well as the DNA damage-related factor Chk2 in vitro and in vivo. In vivo tumorigenicity assays with Ro5203280 intravenous injection showed its potent ability to inhibit tumor growth in mice, with no observable signs of toxicity. These findings suggest the potential usefulness of Ro5203280 as a chemotherapeutic targeting drug for nasopharyngeal carcinoma treatment. (C)2013 AACR.