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Synergistic effects of histone deacetylase inhibitor in combination with mTOR inhibitor in the treatment of prostate carcinoma.
- Source :
-
International journal of molecular medicine [Int J Mol Med] 2013 Feb; Vol. 31 (2), pp. 339-46. Date of Electronic Publication: 2012 Dec 21. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Cell Line, Tumor
Cell Proliferation drug effects
Drug Synergism
Histone Deacetylase Inhibitors pharmacology
Humans
Male
Mice
Mice, Nude
Prostate metabolism
Prostatic Neoplasms pathology
Protein Kinase Inhibitors pharmacology
Sirolimus pharmacology
Sirolimus therapeutic use
Histone Deacetylase Inhibitors therapeutic use
Prostate drug effects
Prostatic Neoplasms drug therapy
Protein Kinase Inhibitors therapeutic use
Sirolimus analogs & derivatives
TOR Serine-Threonine Kinases antagonists & inhibitors
Valproic Acid therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1791-244X
- Volume :
- 31
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- International journal of molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 23292124
- Full Text :
- https://doi.org/10.3892/ijmm.2012.1221