The Histone Deacetylase Inhibitor Trichostatin A Synergistically Resensitizes a Cisplatin Resistant Human Bladder Cancer Cell Line
- 31 March 2011
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of Urology
- Vol. 185 (3), 1102-1111
- https://doi.org/10.1016/j.juro.2010.10.034
Abstract
Cisplatin is the mainstay of treatment for advanced bladder cancer. However, intrinsic or acquired resistance to cisplatin is common, which severely limits its therapeutic potential. We determined the synergistic antitumor effect of cisplatin and the histone deacetylase inhibitor trichostatin A in cisplatin resistant human bladder cancer cells. The cisplatin resistant human bladder cancer cell line T24R2 was exposed to cisplatin and/or trichostatin A. Tumor cell proliferation was examined by cell counting kit assay. Synergism between 2 drugs was examined by the combination index. Changes in cell cycle and apoptosis were determined by flow cytometry. We analyzed the expression of caspase-3, 8 and 9, poly(adenosine diphosphate-ribose) polymerase, p21WAF1/CIP1, cyclin A, B1 and D1, Cdc2c, p-Cdc2c, Cdc25c, p-Cdc25c, cytochrome c, p-Akt, t-Akt, Bcl-2, Bax, Bad, vascular endothelial growth factor and fetal liver kinase-1 by Western blot and colorimetric assay. Based on the combination index and isobole analysis of the Cell Counting Kit-8 assay we observed a strong synergistic antitumor effect between cisplatin and trichostatin A, allowing a 3.5 and 4.9-fold dose reduction in cisplatin and trichostatin A, respectively, while achieving an estimated 90% kill of T24R2 cells. The underlying mechanism could be synergistic cell cycle arrest, induction of caspase mediated apoptosis or up-regulated expression of pro-apoptotic Bad and Bax. Results indicate that trichostatin A may synergistically enhance the antitumor effect of cisplatin and resensitize cisplatin resistant bladder cancer cells. These findings suggest the potential use of histone deacetylase inhibitor as a combination agent to enhance the antitumor effect of cisplatin in patients with advanced bladder cancer.Keywords
This publication has 23 references indexed in Scilit:
- Differential effects of valproic acid on growth, proliferation and metastasis in HTB5 and HTB9 bladder cancer cell linesCancer Letters, 2009
- A Rationally Designed Histone Deacetylase Inhibitor with Distinct Antitumor Activity against Ovarian CancerNeoplasia, 2009
- Enhancement of cisplatin cytotoxicity by SAHA involves endoplasmic reticulum stress-mediated apoptosis in oral squamous cell carcinoma cellsCancer Chemotherapy and Pharmacology, 2009
- Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancerClinical and Translational Oncology, 2008
- Enhancement of cisplatin induced apoptosis by suberoylanilide hydroxamic acid in human oral squamous cell carcinoma cell linesBiochemical Pharmacology, 2007
- Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathwayExperimental & Molecular Medicine, 2006
- Augmentation of cisplatin sensitivity in cisplatin‐resistant human bladder cancer cells by modulating glutathione concentrations and glutathione‐related enzyme activitiesBJU International, 2005
- Differential Effects of Histone Deacetylase Inhibitors in Tumor and Normal Cells—What Is the Toxicological Relevance?Critical Reviews in Toxicology, 2005
- Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.Journal of Clinical Oncology, 1997
- Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitorsAdvances in Enzyme Regulation, 1984