AIMS: To analyze the combined impact of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell growth. MAIN METHODS: PC-3, DU-145 and LNCaP cells were treated with RAD001, VPA or with an RAD001-VPA combination for 3 or 5 days. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT assay, flow cytometry and Western blotting, respectively. Effects of drug treatment on cell signaling pathways were determined. KEY FINDINGS: Separate application of RAD001 or VPA distinctly reduced tumor cell growth and impaired cell cycle progression. Significant additive effects were evoked when both drugs were used in concert. Particularly, the cell cycle regulating proteins cdk1, cdk2, cdk4 and cyclin B were reduced, whereas p21 and p27 were enhanced by the RAD001-VPA combination. Signaling analysis revealed deactivation of EGFr, ERK1/2 and p70S6k. Phosphorylation of Akt was diminished in DU-145 but elevated in PC-3 and LNCaP cells. SIGNIFICANCE: The RAD001-VPA combination exerted profound antitumor properties on a panel of prostate cancer cell lines. Therefore, simultaneous blockage of HDAC and mTOR related pathways should be considered when designing novel therapeutic strategies for treating prostate carcinoma.
AIMS: To analyze the combined impact of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell growth. MAIN METHODS: PC-3, DU-145 and LNCaP cells were treated with RAD001, VPA or with an RAD001-VPA combination for 3 or 5 days. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT assay, flow cytometry and Western blotting, respectively. Effects of drug treatment on cell signaling pathways were determined. KEY FINDINGS: Separate application of RAD001 or VPA distinctly reduced tumor cell growth and impaired cell cycle progression. Significant additive effects were evoked when both drugs were used in concert. Particularly, the cell cycle regulating proteins cdk1, cdk2, cdk4 and cyclin B were reduced, whereas p21 and p27 were enhanced by the RAD001-VPA combination. Signaling analysis revealed deactivation of EGFr, ERK1/2 and p70S6k. Phosphorylation of Akt was diminished in DU-145 but elevated in PC-3 and LNCaP cells. SIGNIFICANCE: The RAD001-VPA combination exerted profound antitumor properties on a panel of prostate cancer cell lines. Therefore, simultaneous blockage of HDAC and mTOR related pathways should be considered when designing novel therapeutic strategies for treating prostate carcinoma.
Authors: Matthew Zibelman; Yu-Ning Wong; Karthik Devarajan; Lois Malizzia; Alycia Corrigan; Anthony J Olszanski; Crystal S Denlinger; Susan K Roethke; Colleen H Tetzlaff; Elizabeth R Plimack Journal: Invest New Drugs Date: 2015-06-20 Impact factor: 3.850
Authors: Leigh Ellis; Kristin Lehet; Swathi Ramakrishnan; Remi Adelaiye; Kiersten M Miles; Dan Wang; Song Liu; Peter Atadja; Michael A Carducci; Roberto Pili Journal: PLoS One Date: 2011-11-07 Impact factor: 3.240
Authors: Kathleen A Wilson-Edell; Mariya A Yevtushenko; Daniel E Rothschild; Aric N Rogers; Christopher C Benz Journal: Breast Cancer Res Treat Date: 2014-02-22 Impact factor: 4.624
Authors: Igor Tsaur; Lukasz Hudak; Jasmina Makarević; Eva Juengel; Jens Mani; Hendrik Borgmann; Kilian M Gust; David Schilling; Georg Bartsch; Karen Nelson; Axel Haferkamp; Roman A Blaheta Journal: J Cell Mol Med Date: 2015-03-26 Impact factor: 5.310
Authors: Jasmina Makarević; Nassim Tawanaie; Eva Juengel; Michael Reiter; Jens Mani; Igor Tsaur; Georg Bartsch; Axel Haferkamp; Roman A Blaheta Journal: J Cell Mol Med Date: 2014-04-30 Impact factor: 5.310