A Novel Small Molecule Aurora Kinase Inhibitor Attenuates Breast Tumor–Initiating Cells and Overcomes Drug Resistance
A Novel Small Molecule Aurora Kinase Inhibitor Attenuates Breast Tumor–Initiating Cells and Overcomes Drug Resistance
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DOI：
10.1158/1535-7163.mct-13-1029
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发表时间：
2014-06
影响因子：
5.7
通讯作者：
Feimeng Zheng;Zi-Jie Long;Zhijie Hou;Yunting Luo;Ling-Zhi Xu;Jianglong Xia;Xiao-Ju Lai;Jiwei Liu-Jiwei-L
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文献类型：
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作者：
Feimeng Zheng;Zi-Jie Long;Zhijie Hou;Yunting Luo;Ling-Zhi Xu;Jianglong Xia;Xiao-Ju Lai;Jiwei Liu-Jiwei-L
化疗耐药是癌症治疗失败的主要原因。肿瘤起始细胞(TIC)因其在化疗耐药和肿瘤复发中的作用而备受关注。在这里，我们评估了小分子极光激酶抑制剂AKI603作为一种新的抗乳腺癌抽动的药物。AKI603显著抑制Aurora-A(AURA)激酶并诱导细胞周期停滞。此外，灌胃AKI603可减少移植瘤的生长。有趣的是，我们发现，对表阿霉素耐药的乳腺癌细胞表达高水平的激活AURA，并具有高CD24Low/CD44High TIC群体。AKI603对AURA激酶的抑制可消除表阿霉素性抽动的致富作用。此外，AKI603还抑制了细胞形成乳房的能力，并抑制了自我更新基因(β-连环蛋白、c-Myc、Sox2和Oct4)的表达。因此，我们的工作表明，小分子Aurora激酶抑制剂AKI603可能在临床上用于克服乳腺癌常规化疗药物诱导的耐药性。《摩尔癌症》；13(8)；1991-2003年。©2014 AACR。
Chemoresistance is a major cause of cancer treatment failure. Tumor-initiating cells (TIC) have attracted a considerable amount of attention due to their role in chemoresistance and tumor recurrence. Here, we evaluated the small molecule Aurora kinase inhibitor AKI603 as a novel agent against TICs in breast cancer. AKI603 significantly inhibited Aurora-A (AurA) kinase and induced cell-cycle arrest. In addition, the intragastric administration of AKI603 reduced xenograft tumor growth. Interestingly, we found that breast cancer cells that were resistant to epirubicin expressed a high level of activated AurA and also have a high CD24Low/CD44High TIC population. The inhibition of AurA kinase by AKI603 abolished the epirubicin-induced enrichment of TICs. Moreover, AKI603 suppressed the capacity of cells to form mammosphere and also suppressed the expression of self-renewal genes (β-catenin, c-Myc, Sox2, and Oct4). Thus, our work suggests the potential clinical use of the small molecule Aurora kinase inhibitor AKI603 to overcome drug resistance induced by conventional chemotherapeutics in breast cancer. Mol Cancer Ther; 13(8); 1991–2003. ©2014 AACR.