Human polo-like kinase 1 (Plk1) is a key player in different stages of mitosis and modulates the spindle checkpoint at the metaphase-anaphase transition. Overexpression of Plk1 is observed in various human tumors and it is a negative prognostic factor in patients suffering from diverse cancers. We used phosphorothioate antisense oligonucleotides (ASO) targeted against Plk1, together with paclitaxel, carboplatin, and Herceptin, for the treatment of breast cancer cells to identify conditions for enhanced drug sensitivity. After transfection of the breast cancer cell lines BT-474, MCF-7, and MDA-MB-435 with Plk1-specific ASOs, paclitaxel, carboplatin, or Herceptin was added and cell proliferation, cell cycle distribution, and apoptosis were measured. Whereas the dual treatment of breast cancer cells with Plk1-specific ASOs with carboplatin or Herceptin caused only a limited antiproliferative effect in breast cancer cells, we observed synergistic effects after combination of low doses of Plk1-specific ASOs with paclitaxel, which is used in a variety of clinical anticancer regimens. Plk1-specific ASOs also acted synergistically with paclitaxel in the arrest of the cell cycle at the G 2 -M phase and in the induction of apoptosis. Interestingly, 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 3 weeks of treatment compared with either agent alone. This study suggests that antisense inhibitors against Plk1 at well-tolerated doses may be considered as highly efficient promoters for the antineoplastic potential of taxanes, such as paclitaxel, causing synergistic effects in breast cancer cells. (Cancer Res 2006; 66(11): 5836-46)

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.

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