Abstract
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.
Highlights
Paclitaxel was first derived in 1967 from the bark of trees of the genus, Taxus; its antitumor activity has been proven by numerous pharmacological and clinical studies [1]
We discovered that Trichostatin A (TSA) effectively remodeled the aberrant extracellular signal-regulated kinase (ERK) pathway found in advanced urothelial carcinoma (UC) cells
As a proof-of-principle experiment, we demonstrated that TSA—an experimental histone deacetylase (HDAC) inhibitor—is promising for the treatment of advanced UC
Summary
Paclitaxel was first derived in 1967 from the bark of trees of the genus, Taxus; its antitumor activity has been proven by numerous pharmacological and clinical studies [1]. The rapidly accelerated fibrosarcoma (RAF) kinase/mitogen-activated protein kinase (MEK)/ERK pathway can govern drug resistance, apoptosis, and sensitivity to chemotherapy and targeted therapy and was reported to be a therapeutic target for cancer treatment [23]. TSA Suppression of ERK Pathway Activation Following Paclitaxel Treatment in Human UC Cells. TToo oovveerrccoommee tthhee cchheemmootthheerraappyy rreessiissttaannccee ooff aaddvvaanncceedd oorr mmeettaassttaattiicc UUCC,, tthhee uussee ooff TTSSAA aass aa ccoommbbiinnaattiioonn aaggeenntt ttoo iinnfflluueennccee ggeennee eexxpprreessssiioonn aanndd eennhhaannccee tthhee aannttiittuummoorr eeffffeecctt ooff ggeemmcciittaabbiinnee oonn aaddvvaanncceedd UUCC wwaass eexxpplloorreedd [[2211]]. The Food and Drug Administration has approved vorinostat and romidepsin with indications for refractory cutaneous T-cell lymphoma [35,36] Some of these clinically approved HDAC inhibitors likely share antitumor properties with TSA.
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