. 2018 Dec;96(12):1307-1318.

doi: 10.1007/s00109-018-1697-7. Epub 2018 Oct 4.

Trichostatin A, a histone deacetylase inhibitor, induces synergistic cytotoxicity with chemotherapy via suppression of Raf/MEK/ERK pathway in urothelial carcinoma

Wei-Chou Lin¹, Fu-Shun Hsu^{2

3}, Kuan-Lin Kuo^{4

5}, Shing-Hwa Liu⁴, Chia-Tung Shun¹, Chung-Sheng Shi⁶, Hong-Chiang Chang⁵, Yu-Chieh Tsai⁷, Ming-Chieh Lin⁸, June-Tai Wu⁸, Yu Kuo^{8

9}, Po-Ming Chow⁵, Shih-Ming Liao⁵, Shao-Ping Yang⁵, Jo-Yu Hong⁵, Kuo-How Huang^{10

11}

Affiliations

¹ Department of Pathology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.
² Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
³ Department of Urology, New Taipei City Hospital, New Taipei City, Taiwan.
⁴ Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁵ Department of Urology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁷ Department of Oncology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.
⁸ Graduate Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁹ Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁰ Department of Urology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan. khhuang123@ntu.edu.tw.
¹¹ Department of Urology, College of Medicine, National Taiwan University, No 1 Jen-Ai Road, Taipei, 10051, Taiwan. khhuang123@ntu.edu.tw.

PMID: 30288546
DOI: 10.1007/s00109-018-1697-7

Trichostatin A, a histone deacetylase inhibitor, induces synergistic cytotoxicity with chemotherapy via suppression of Raf/MEK/ERK pathway in urothelial carcinoma

Wei-Chou Lin et al. J Mol Med (Berl). 2018 Dec.

. 2018 Dec;96(12):1307-1318.

doi: 10.1007/s00109-018-1697-7. Epub 2018 Oct 4.

Authors

Affiliations

¹ Department of Pathology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.
² Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
³ Department of Urology, New Taipei City Hospital, New Taipei City, Taiwan.
⁴ Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁵ Department of Urology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁷ Department of Oncology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.
⁸ Graduate Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁹ Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁰ Department of Urology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan. khhuang123@ntu.edu.tw.
¹¹ Department of Urology, College of Medicine, National Taiwan University, No 1 Jen-Ai Road, Taipei, 10051, Taiwan. khhuang123@ntu.edu.tw.

PMID: 30288546
DOI: 10.1007/s00109-018-1697-7

Erratum in

Correction to: Trichostatin A, a histone deacetylase inhibitor, induces synergistic cytotoxicity with chemotherapy via suppression of Raf/MEK/ERK pathway in urothelial carcinoma.
Lin WC, Hsu FS, Kuo KL, Liu SH, Shun CT, Shi CS, Chang HC, Tsai YC, Lin MC, Wu JT, Kuo Y, Chow PM, Liao SM, Yang SP, Hong JY, Huang KH. Lin WC, et al. J Mol Med (Berl). 2019 Mar;97(3):435-436. doi: 10.1007/s00109-019-01748-2. J Mol Med (Berl). 2019. PMID: 30741319

Abstract

In this study, we aimed to investigate the antitumor effects of trichostatin A (TSA), an antifungal antibiotic that inhibits histone deacetylase (HDAC) family of enzymes, alone or in combination with anyone of the three chemotherapeutic agents (cisplatin, gemcitabine, and doxorubicin) for the treatment of human urothelial carcinoma (UC). Two high-grade human UC cell lines (T24 and NTUB1) were used. Cytotoxicity and apoptosis were assessed by MTT assay and flow cytometry, respectively. The expression of phospho-c-Raf, phospho-MEK1/2, and phospho-ERK1/2 was measured by western blotting. ERK siRNA knockdown and the specific MEK inhibitor U0126 were used to examine the role of Raf/MEK/ERK signaling pathway in combined cytotoxicity of TSA and chemotherapy. TSA co-treatment with any one of the three chemotherapeutic agents induced synergistic cytotoxicity (combination index < 1) and concomitantly suppressed chemotherapeutic drug-induced activation of Raf-MEK-ERK pathway. Combination of ERK siRNA knockdown and treatment with the specific MEK inhibitor (U0126) enhanced the cytotoxic effects of the chemotherapy on UC cells. These observations were confirmed in a xenograft nude mouse model. Moreover, activated Raf/MEK/ERK pathway was observed in human bladder UC specimens from patients with chemoresistant status. In conclusion, TSA elicits a synergistic cytotoxic response in combination with chemotherapy via targeting the Raf/MEK/ERK pathway. TSA elicits synergistic cytotoxic response in combination with three DNA-damaging drugs (cisplatin, gemcitabine, and doxorubicin). Activated Raf/MEK/ERK pathway is involved in chemoresistant mechanism of UC. Combining chemotherapeutic agents with HDAC inhibitor (TSA) or with targeting Raf/MEK/ERK pathway is promising to circumvent chemoresistance in UCs.

Keywords: Chemotherapy; Drug resistance; Histone deacetylase inhibitor; Trichostatin A; Urothelial carcinoma.

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References

1. Cell Cycle. 2010 May;9(9):1781-91 - PubMed
1. Oncogene. 2005 Aug 4;24(33):5218-25 - PubMed
1. Radiat Res. 2013 Apr;179(4):383-92 - PubMed
1. Anticancer Drugs. 2011 Nov;22(10):1002-9 - PubMed
1. Int J Cancer. 1973 May;11(3):765-73 - PubMed

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Trichostatin A, a histone deacetylase inhibitor, induces synergistic cytotoxicity with chemotherapy via suppression of Raf/MEK/ERK pathway in urothelial carcinoma

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Trichostatin A, a histone deacetylase inhibitor, induces synergistic cytotoxicity with chemotherapy via suppression of Raf/MEK/ERK pathway in urothelial carcinoma

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