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Open AccessArticle

Histone Deacetylase Inhibitor, Trichostatin A, Synergistically Enhances Paclitaxel-Induced Cytotoxicity in Urothelial Carcinoma Cells by Suppressing the ERK Pathway

1
Department of Urology, New Taipei City Hospital, New Taipei City 112, Taiwan
2
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 106, Taiwan
3
Department of Dermatology, National Taiwan University Hospital, Taipei 100, Taiwan
4
Department of Dermatology, Chang Gung Memorial Hospital, Keelung 204, Taiwan
5
College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
6
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 106, Taiwan
7
Department of Urology, National Taiwan University Hospital, Taipei 100, Taiwan
8
Department of Pathology, National Taiwan University Hospital, Taipei 100, Taiwan
9
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(5), 1162; https://doi.org/10.3390/ijms20051162
Received: 28 January 2019 / Revised: 22 February 2019 / Accepted: 3 March 2019 / Published: 7 March 2019
(This article belongs to the Section Molecular Pharmacology)
Trichostatin A (TSA), an antifungal antibiotic derived from Streptomyces, inhibits mammalian histone deacetylases, and especially, selectively inhibits class I and II histone deacetylase (HDAC) families of enzymes. TSA reportedly elicits an antiproliferative response in multifarious tumors. This study investigated the antitumor effects of TSA alone and in combination with paclitaxel when applied to two high-grade urothelial carcinoma (UC) cell lines (BFTC-905 and BFTC-909). Fluorescence-activated cell sorting, flow cytometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay were used to assess TSA’s cytotoxicity and effects on apoptosis induction. TSA induced synergistic cytotoxicity, when combined with paclitaxel (combination index < 1), resulted in concomitant suppression of paclitaxel-induced activation of phospho-extracellular signal-regulated kinase (ERK) 1/2. A xenograft nude mouse model confirmed that TSA enhances the antitumor effects of paclitaxel. These findings demonstrate that the administration of TSA in combination with paclitaxel elicits a synergistic cytotoxic response. The results of this study indicate that the chemoresistance of UC could be circumvented by combining HDAC inhibitors to target the ERK pathway. View Full-Text
Keywords: urothelial carcinoma; trichostatin A; histone deacetylase inhibitor; chemotherapy; paclitaxel urothelial carcinoma; trichostatin A; histone deacetylase inhibitor; chemotherapy; paclitaxel
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MDPI and ACS Style

Hsu, F.-S.; Wu, J.-T.; Lin, J.-Y.; Yang, S.-P.; Kuo, K.-L.; Lin, W.-C.; Shi, C.-S.; Chow, P.-M.; Liao, S.-M.; Pan, C.-I; Hong, J.-Y.; Chang, H.-C.; Huang, K.-H. Histone Deacetylase Inhibitor, Trichostatin A, Synergistically Enhances Paclitaxel-Induced Cytotoxicity in Urothelial Carcinoma Cells by Suppressing the ERK Pathway. Int. J. Mol. Sci. 2019, 20, 1162. https://doi.org/10.3390/ijms20051162

AMA Style

Hsu F-S, Wu J-T, Lin J-Y, Yang S-P, Kuo K-L, Lin W-C, Shi C-S, Chow P-M, Liao S-M, Pan C-I, Hong J-Y, Chang H-C, Huang K-H. Histone Deacetylase Inhibitor, Trichostatin A, Synergistically Enhances Paclitaxel-Induced Cytotoxicity in Urothelial Carcinoma Cells by Suppressing the ERK Pathway. International Journal of Molecular Sciences. 2019; 20(5):1162. https://doi.org/10.3390/ijms20051162

Chicago/Turabian Style

Hsu, Fu-Shun; Wu, June-Tai; Lin, Jing-Yi; Yang, Shao-Ping; Kuo, Kuan-Lin; Lin, Wei-Chou; Shi, Chung-Sheng; Chow, Po-Ming; Liao, Shih-Ming; Pan, Chun-I; Hong, Jo-Yu; Chang, Hong-Chiang; Huang, Kuo-How. 2019. "Histone Deacetylase Inhibitor, Trichostatin A, Synergistically Enhances Paclitaxel-Induced Cytotoxicity in Urothelial Carcinoma Cells by Suppressing the ERK Pathway" Int. J. Mol. Sci. 20, no. 5: 1162. https://doi.org/10.3390/ijms20051162

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