Downregulation of PLK1 elevates chemosensitivity of various breast cancer cell lines in vitro and in vivo

13169 Background: A central role for polo-like kinases (PLK) in regulating mitosis has been shown in different species. Overexpression of PLK1 is observed in various human tumors, and it is a negative prognostic factor in patients suffering from diverse cancers. In order to reduce side-effects exerted by commonly used anti-neoplastic agents and to enhance chemosensitivity of different breast cancer cell lines, we used phosphorothioate antisense oligonucleotides (ASOs) targeted against PLK1 together with Paclitaxel, Carboplatin and Herceptin. Methods: We used different HER2-positive and -negative breast cancer cell lines (BT-474, MCF-7, MDA-MB-435) to define the role of reduced PLK1 expression for the necessary dose of anti-neoplastic agents. After transfection with PLK1-specific ASOs these agents were added and cell proliferation, cell cycle distribution, and apoptosis were measured. Results: We observed synergistic effects after combination of very low doses of PLK1-specific ASOs with Paclitaxel and Herceptin. Using Carboplatin we could only observe a synergistic effect in MDA-MB-435 cells. Downregulation of PLK1 levels led to an elevated percentage of cells in G2/M. Apoptosis and G2/M arrest were increased after combination of PLK1-specific ASOs with Paclitaxel in MDA-MB-435 cells. In a human Xenograft experiment using MDA-MB-435 cells the combination of PLK1-ASOs with Paclitaxel led to synergistic reduction of tumor growth after three weeks treatment compared to either agent alone. Conclusion: This study suggests that antisense inhibitors against PLK1 at well tolerated doses may be considered as cancer therapeutic agents which elevate chemosensitivity especially against Paclitaxel in very low doses with a significant better outcome than each agent alone. No significant financial relationships to disclose.