BackgroundCapsaicin (8-methyl-N-vanillyl-6-nonenamide) is one of the main pungent components of chili peppers and has been shown to exert various effects on numerous physiological processes. Recent studies have focused on the chemopreventive effects of capsaicin, which can combat growth in various human cancer cell systems. The tribbles-related protein 3 (TRIB3) is evolutionarily conserved from Drosophila to humans. In the latter, TRIB3 is a key determinant in numerous cellular processes, including apoptosis.PurposeThe aim of this study was to examine the importance of TRIB3 in the antitumor efficacy of capsaicin in human cancer cells, and further assess potential mechanism(s) underlying the capsaicin-induced upregulation of TRIB3.MethodsHuman cancer cell lines were treated with capsaicin, then evaluated for levels of TRIB3 and molecules related to apoptosis or signaling pathways. The impact of TRIB3 on capsaicin-induced apoptosis was investigated using si-RNA or overexpression of TRIB3.ResultsIt is the first time to show that TRIB3 is targeted by capsaicin to promote apoptosis. Capsaicin promotes apoptotic cell death by upregulating TRIB3 expression in cancer cells. Overexpression of TRIB3 enhances capsaicin-induced apoptosis, and TRIB3 knockdown experiments demonstrate that the effect of capsaicin in apoptotic cell death is correlated with the induction of TRIB3 in cancer cells. Finally, enhancements in gene expression and protein stability are involved in the capsaicin-induced upregulation of TRIB3.ConclusionOur results show that the capsaicin-induced upregulation of TRIB3 triggers apoptosis and thereby contributes to the suppression of cell growth in cancer cell lines.

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.

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