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The prostate cancer blocking potential of the histone deacetylase inhibitor LBH589 is not enhanced by the multi receptor tyrosine kinase inhibitor TKI258

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Summary

Pharmacologic options for patients with castration-resistant prostate cancer are limited. It has been suggested that targeting intracellular molecules, which have been altered during neoplastic development, may slow tumor growth. Therefore, the growth-blocking potential of the histone deacetylase-inhibitor LBH589 and the multiple tyrosine kinase-inhibitor TKI258, applied alone or in combination, was investigated in a panel of prostate cancer cell lines. PC-3, DU-145 or LNCaP cells were treated with various concentrations of LBH589 and/or TKI258. Tumor cell growth, cell cycle regulating proteins, HDAC3- and HDAC4-expression and histone H3 and H4 acetylation were then evaluated by MTT assay and Western blotting. LBH589 dose-dependently blocked prostate cancer cell growth. In contrast, TKI258 did not down-regulate tumor cell growth up to a 1,000 nM dosage. LBH589 elevated histone H3 and H4 acetylation. The cell cycle regulators cyclin B, cyclin D1, cdk1 and cdk4 were down-regulated in PC-3, whereas the suppressor proteins p21 and p27 were up-regulated in LNCaP by LBH589. TKI258 up-regulated p27 in PC-3 or p21 in LNCaP and additionally elevated cyclin B, cyclin D1, cdk1 and cdk4 in both cell lines. Presumably, the increase in cyclin and cdk caused by TKI258 counteracts the benefit of p21 or p27 up-regulation, resulting in TKI258 non-responsiveness. The LBH589/TKI258-combination was not superior to the LBH589 single-drug use in terms of growth reduction. Obviously, TKI258 did not enhance the sensitivity of prostate cancer cells towards an HDAC based regimen. Therefore, the LBH589/TKI258-combination probably does not provide an optimum strategy in fighting advanced prostate cancer.

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Acknowledgements

We would like to thank Karen Nelson for critically reading the manuscript.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Urology, Johann Wolfgang Goethe-University, Interdisciplinary Science Building, Building 25, Room 204, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Stefan Vallo, Jens Mani, Matthias Stastny, Jasmina Makarević, Eva Juengel, Igor Tsaur, Georg Bartsch, Axel Haferkamp & Roman A. Blaheta

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  1. Stefan Vallo
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  2. Jens Mani
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  3. Matthias Stastny
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Correspondence to Roman A. Blaheta.

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Stefan Vallo and Jens Mani contributed equally to this work.

Axel Haferkamp and Roman A. Blaheta contributed equally as senior authors.

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Vallo, S., Mani, J., Stastny, M. et al. The prostate cancer blocking potential of the histone deacetylase inhibitor LBH589 is not enhanced by the multi receptor tyrosine kinase inhibitor TKI258. Invest New Drugs 31, 265–272 (2013). https://doi.org/10.1007/s10637-012-9851-5

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