A new antifungal antibiotic, trichostatin.

Tsuji, Naoki; Kobayashi, Masaaki; Nagashima, K.; Wakisaka, Yoshiharu; Koizumi, Kenzo

doi:10.7164/antibiotics.29.1

Cited by 318 publications

(184 citation statements)

References 2 publications

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“…Trichostatin A (TSA), initially isolated as fungistatic antibiotics from Streptomyces hygroscopicus (Tsuji et al, 1979), is a potent inhibitor of HDAC activity at nanomolar concentrations. TSA has been suggested to block the catalytic reaction by chelating a zinc ion in the active site pocket through its hydroxamic acid group (Marks et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway

Kim

Kim²,

Yang³

et al. 2006

Exp Mol Med

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Trichostatin A (TSA), originally developed as an antifungal agent, is one of potent histone deacetylase (HDAC) inhibitors, which are known to cause growth arrest and apoptosis induction of transformed cells, including urinary bladder, breast, prostate, ovary, and colon cancers. However, the effect of HDAC inhibitors on human non-small cell lung cancer cells is not clearly known yet. Herein, we demonstrated that treatment of TSA resulted in a significant decrease of the viability of H157 cells in a dose-dependent manner, which was revealed as apoptosis accompanying with nuclear fragmentation and an increase in sub-G 0 /G 1 fraction. In addition, it induced the expression of Fas/FasL, which further triggered the activation of caspase-8. Catalytic activation of caspase-9 and decreased expression of anti-aptototic Bcl-2 and Bcl-XL proteins were observed in TSA-treated cells. Catalytic activation of caspase-3 by TSA was further confirmed by cleavage of pro-caspase-3 and intracellular substrates, including poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated deoxyribonuclease (ICAD). In addition, a characteristic phenomenon of mitochondrial dysfunction, including mitochondrial membrane potential transition and release of mitochondrial cytochrome c into the cytosol was apparent in TSA-treated cells. Taken together, our data indicate that inhibition of HDAC by TSA induces the apoptosis of H157 cells through signaling cascade of Fas/FasL-mediated extrinsic and mitocondria-mediated intrinsic caspases pathway.

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Section: Introductionmentioning

confidence: 99%

Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway

Kim

Kim²,

Yang³

et al. 2006

Exp Mol Med

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“…Trichostatin A (TSA) 1 was first discovered as an antifungal agent (7). Later, it was characterized as a noncompetitive inhibitor of histone deacetylase (8).…”

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confidence: 99%

Participation of p97Eps8 in Src-mediated Transformation

Leu

Yeh

Huang

et al. 2004

Journal of Biological Chemistry

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Histone acetylase and histone deacetylase are two crucial enzymes that determine the structure of chromatin, regulating gene expression. In this study, we observed that trichostatin A (TSA), a specific histone deacetylase inhibitor, could effectively inhibit the growth of v-Src-transformed (IV5) cells and abrogate their ability to form colonies in soft agar. Further analysis demonstrated that, although TSA reduced the expression of Eps8 in a dose-and time-dependent manner, both the protein expression and kinase activity of v-Src remained constant, and the abundance and phosphotyrosine levels of Src substrates, including cortactin, focal adhesion kinase, p130 Cas , paxillin, and Shc, were not altered. Notably, removal of TSA from the medium restored not only the expression of Eps8, but also cellular growth. Northern and reverse transcription-PCR analyses revealed the significant reduction of eps8 transcripts in TSA-treated IV5 cells relative to control cells. When active Src-expressing chicken embryonic cells were forced to overexpress p97 Eps8 , they became resistant to TSA-mediated anti-proliferation. Furthermore, using small interference RNA of eps8, we demonstrated the requirement for Eps8 in IV5 cell proliferation. Thus, our results highlight a critical role for p97 Eps8 in TSA-exerted growth inhibition of v-Src-transformed cells.

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“…Trichostatin A (TSA) is a metabolite from Streptomyces hygroscopicus 47 that inhibits deacetylase activity and that has been linked to another degradative pathway, autophagy. 48 Studies examined its impact on Tir levels within WT and Nck-deficient cells.…”

Section: Trichostatin a Treatment Increases The Epec Attachment Tir mentioning

confidence: 99%

Nck adaptors, besides promoting N-WASP mediated actin-nucleation activity at pedestals, influence the cellular levels of enteropathogenicEscherichia coliTir effector

Nieto-Pelegrín

Kenny

Martı́nez-Quiles

2014

Cell Adhesion & Migration

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Enteropathogenic Escherichia coli (EPEC) binding to human intestinal cells triggers the formation of diseaseassociated actin rich structures called pedestals. The latter process requires the delivery, via a Type 3 secretion system, of the translocated Intimin receptor (Tir) protein into the host plasma membrane where binding of a host kinasemodified form to the bacterial surface protein Intimin triggers pedestal formation. Tir-Intimin interaction recruits the Nck adaptor to a Tir tyrosine phosphorylated residue where it activates neural Wiskott-Aldrich syndrome protein (N-WASP); initiating the major pathway to actin polymerization mediated by the actin-related protein (Arp) 2/3 complex. Previous studies with Nck-deficient mouse embryonic fibroblasts (MEFs) identified a key role for Nck in pedestal formation, presumed to reflect a lack of N-WASP activation. Here, we show the defect relates to reduced amounts of Tir within Nck-deficient cells. Indeed, Tir delivery and, thus, pedestal formation defects were much greater for MEFs than HeLa (human epithelial) cells. Crucially, the levels of two other effectors (EspB/EspF) within Nck-deficient MEFs were not reduced unlike that of Map (Mitochondrial associated protein) which, like Tir, requires CesT chaperone function for efficient delivery. Interestingly, drugs blocking various host protein degradation pathways failed to increase Tir cellular levels unlike an inhibitor of deacetylase activity (Trichostatin A; TSA). Treatments with TSA resulted in significant recovery of Tir levels, potentiation of actin polymerization and improvement in bacterial attachment to cells. Our findings have important implications for the current model of Tir-mediated actin polymerization and opens new lines of research in this area.

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A new antifungal antibiotic, trichostatin.

Abstract: A new antibiotic, trichostatin, was isolated from the metabolites of strains of Streptomyces hygroscopicus.It is active against trichophytons and some fungi. The structure was determined to be a derivative of a primary hydroxamic acid by chemical and spectroscopic evidences.

Cited by 318 publications

References 2 publications

Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway

Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway

Participation of p97Eps8 in Src-mediated Transformation

Nck adaptors, besides promoting N-WASP mediated actin-nucleation activity at pedestals, influence the cellular levels of enteropathogenicEscherichia coliTir effector

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