Trichostatin A, a histone deacetylase inhibitor, induces synergistic cytotoxicity with chemotherapy via suppression of Raf/MEK/ERK pathway in urothelial carcinoma
Journal
Journal of Molecular Medicine
Journal Volume
96
Journal Issue
12
Pages
1307-1318
Date Issued
2018
Author(s)
Hsu F.-S.
Kuo K.-L.
Shi C.-S.
Lin M.-C.
Wu J.-T.
Kuo Y.
Liao S.-M.
Yang S.-P.
Hong J.-Y.
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. ? 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
SDGs
Other Subjects
1,4 diamino 1,4 bis(2 aminophenylthio) 2,3 dicyanobutadiene; cisplatin; doxorubicin; gemcitabine; mitogen activated protein kinase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; Raf protein; small interfering RNA; trichostatin A; antineoplastic agent; cisplatin; deoxycytidine; doxorubicin; gemcitabine; histone deacetylase inhibitor; hydroxamic acid; protein kinase; protein kinase inhibitor; small interfering RNA; trichostatin A; animal experiment; animal model; antineoplastic activity; apoptosis; Article; cancer combination chemotherapy; cancer resistance; cell viability; cell viability assay; concentration response; drug cytotoxicity; drug efficacy; drug potentiation; enzyme activation; flow cytometry; gene knockdown; human; human cell; in vitro study; in vivo study; MAPK signaling; mouse; MTT assay; nonhuman; NTUB1 cell line; protein function; T24 cell line; transitional cell carcinoma; tumor xenograft; Western blotting; animal; cell survival; drug effect; drug potentiation; genetics; MAPK signaling; metabolism; nude mouse; tumor cell line; urinary tract tumor; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Cisplatin; Deoxycytidine; Doxorubicin; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; MAP Kinase Signaling System; Mice, Nude; Protein Kinase Inhibitors; Protein Kinases; RNA, Small Interfering; Urologic Neoplasms
Publisher
Springer Verlag
Type
journal article