aki603 and Breast-Neoplasms

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 CD24(Low)/CD44(High) 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.

Topics: Animals; Antineoplastic Agents; Aurora Kinase A; Breast Neoplasms; Cell Cycle Checkpoints; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Epirubicin; Female; Humans; MCF-7 Cells; Mice, Nude; Neoplastic Stem Cells; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Spheroids, Cellular; Tumor Burden; Xenograft Model Antitumor Assays