Abstract
Abstract Polo-like kinase 1 (Plk1) plays a central role in the cell division in eukaryotic cells during mitosis and is overexpressed in many cancers, including prostate cancer (PCa). Early studies show that the Plk1 inhibitors BI 2536 and BI 6727 are effective in the treatment of different cancers. Plk1 inhibitors have been demonstrated to arrest cancer cells effectively, while most normal, non-dividing healthy cells remain unaffected, thereby proving to be very specific with reduced toxicity. Both drugs are for this reason currently tested in diverse clinical trials for both solid and liquid tumors with encouraging results. We tested whether BI 2536 and BI 6727 can be effectively used to target PCa. PCa cell lines DU-145, LNCaP, and PC3 cells were treated for 48 hours with different concentrations of Plk1 inhibitors ranging from 10nM-1μM, and proliferation was assayed using an MTS-assay. While BI 6727 was very effective at very low nanomolar range for DU-145 and LNCaP cells (DU-145 IC50 < 10nM; LNCaP IC50 = 10nM), BI 2536 was effective at higher concentrations in both cell lines (DU-145, IC50=10nM; LNCaP IC50= 75nM). PC3 cells were more resistant to Plk1 inhibitors exhibiting IC50 of 200nM for BI 2536 and 750nM for BI 6727. Both Plk1 inhibitors induced apoptosis at their effective concentration as judged by PARP cleavage. Differential response of prostate cancer cell lines to Plk1 inhibitors may be due to differences in Plk1 expression, or due to differences in response to the activation of the spindle assembly checkpoint. Since Plk1 inhibitors target the mitotic phase of the cell cycle, we hypothesized that combination of Plk1 inhibitors with agents that arrest cell cycle in the G1 or G2/M phase may have an enhanced anti-proliferative effect on prostate cancer. We therefore tested the effect of a combination of generic histone deacetylase (HDAC) inhibitors with Plk1 inhibitors on proliferation of PCa cells. We administered different combinations and concentrations of BI 2536 and BI 6727 with generic HDAC inhibitors, Vorinostat (SAHA) and valproic acid, to PCa cells. MTS-assays and clonogenic assays were performed to determine proliferation and survival, respectively. Our results reveal that BI 6727 in combination with HDAC inhibitors has an additive/synergistic effect as compared to single agents; however, combinations of HDAC inhibitors with BI 2536 only showed an additive effect when PCa cells were drugged at low concentrations of BI 2536 (10nM for DU145, 50nM for LNCaP, and 50nM for PC3 cells), while higher concentrations didn't show any significant enhancement compared to a single agent. We conclude that Plk1 inhibitors, especially BI 6727 in combination with a generic HDAC inhibitor, may have a better therapeutic outcome for the treatment of PCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5414.
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