Synergistic effects of histone deacetylase inhibitor in combination with mTOR inhibitor in the treatment of prostate carcinoma

  • Authors:
    • Paul Thelen
    • Lisa Krahn
    • Felix Bremmer
    • Arne  Strauss
    • Ralph Brehm
    • Hagen Loertzer
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  • Published online on: December 21, 2012     https://doi.org/10.3892/ijmm.2012.1221
  • Pages: 339-346
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Abstract

The aim of this study was to elucidate whether the treatment of a prostate carcinoma cell line (LNCaP) and LNCaP-derived tumors with the histone deacetylase (HDAC) inhibitor valproate in combination with the mammalian target of rapamycin (mTOR) inhibitor temsirolimus resulted in synergistic effects on cell proliferation and tumor growth. LNCaP cells were treated with valproate, temsirolimus or a combination of both. The proliferation rates and the expression of key markers of tumorigenesis were evaluated. In in vivo experiments, LNCaP cells were implanted into immune-suppressed male nude mice. Mice were treated with valproate (per os), temsirolimus (intravenously) or with a combination of both. Tumor volumes were calculated and mRNA expression was quantified. The incubation of LNCaP cells with the combination of valproate and temsirolimus resulted in a decrease of cell proliferation with an additive effect of both drugs in comparison to the single treatment. In particular, the combined application of valproate and temsirolimus led to a significant upregulation of insulin-like growth factor-binding protein-3 (IGFBP-3), which mediates apoptosis and inhibits tumor cell proliferation. In the mouse model, we found no significant differences in tumor growth between the different treatment arms but immunohistological analyses showed that tumors treated with a combination of valproate and temsirolimus, but not with the single drugs alone, exhibited a significant lower proliferation capacity.
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February 2013
Volume 31 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Thelen P, Krahn L, Bremmer F, Strauss A, Brehm R and Loertzer H: Synergistic effects of histone deacetylase inhibitor in combination with mTOR inhibitor in the treatment of prostate carcinoma. Int J Mol Med 31: 339-346, 2013
APA
Thelen, P., Krahn, L., Bremmer, F., Strauss, A., Brehm, R., & Loertzer, H. (2013). Synergistic effects of histone deacetylase inhibitor in combination with mTOR inhibitor in the treatment of prostate carcinoma. International Journal of Molecular Medicine, 31, 339-346. https://doi.org/10.3892/ijmm.2012.1221
MLA
Thelen, P., Krahn, L., Bremmer, F., Strauss, A., Brehm, R., Loertzer, H."Synergistic effects of histone deacetylase inhibitor in combination with mTOR inhibitor in the treatment of prostate carcinoma". International Journal of Molecular Medicine 31.2 (2013): 339-346.
Chicago
Thelen, P., Krahn, L., Bremmer, F., Strauss, A., Brehm, R., Loertzer, H."Synergistic effects of histone deacetylase inhibitor in combination with mTOR inhibitor in the treatment of prostate carcinoma". International Journal of Molecular Medicine 31, no. 2 (2013): 339-346. https://doi.org/10.3892/ijmm.2012.1221