Disease relevance of WS 1228A

• Exogenous arachidonic acid caused apoptosis in colon cancer and other cell lines, as did triacsin C, a FACL inhibitor [1].
• Second, when HIV Gag protein was expressed in the presence of triacsin C (0-48 microM), Gag myristoylation was inhibited in a dose-dependent manner [2].
• We have investigated the effects of triacsin C, an inhibitor of long chain acyl-CoA synthetase, on release of HIV Gag virus-like particle (VLP) produced using the recombinant baculovirus system [2].
• The concentrations of triacsin A required for 50% inhibition of acyl-CoA synthetase from Pseudomonas aeruginosa and from rat liver are 17 and 18 microM, and those of triacsin C are 3.6 and 8.7 microM, respectively [3].

High impact information on WS 1228A

• Triacsin C, an inhibitor of fatty acyl-CoA synthetase, prevented the increase in PFK activity and the lowered G6P content [4].
• 5. Like purified FATP1, FATP4 was insensitive to inhibition by triacsin C but was sensitive to feedback inhibition by acyl-CoA [5].
• Because inhibition of palmitate metabolism by the acyl-CoA synthetase inhibitor triacsin C did not abolish IL-6 expression, it appears that the palmitate molecule per se exerts the observed effects [6].
• Palmitate-induced apoptosis was enhanced by the fat oxidation inhibitor etomoxir, whereas it was reduced by fatty-acyl CoA synthase inhibitor triacsin C [7].
• Interestingly, the addition of triacsin C, a potent inhibitor of acyl-CoA synthetase, to etomoxir-treated C2C12 skeletal muscle cells did not prevent the down-regulation in PPARalpha mRNA levels, suggesting that the active form of the drug, etomoxir-CoA, was not involved [8].

Biological context of WS 1228A

• Triacsin C, an inhibitor of fatty acyl-CoA synthetase, and troglitazone, an enhancer of FFA oxidation in ZDF islets, both blocked DNA laddering [9].
• Triacsin C blocked esterification, thereby rendering the membranes unable to metabolize this radiolabel [10].
• The acyl:CoA synthetase blocker, triacsin C, inhibited esterification but also led to an increase in the hydroxylation of the label [10].
• The alternative, pharmacologic approach for perturbing lipid metabolism was to use triacsin C to inhibit long-chain acyl-CoA synthetase [11].
• Although it has been hypothesized that the TG accumulation is caused by a functional defect in cytosolic lipase activity, we were able to expose TG hydrolysis in NLSD cells by using triacsin C, an inhibitor of acyl-CoA synthetase that blocks the reincorporation of hydrolyzed fatty acids into glycerolipids [12].

Anatomical context of WS 1228A

• Indeed, triacsin C-treated membranes bound (Kd = 3.8 nM) 5-[3H]oxoETE specifically and reversibly to 86 pmol of sites per 25 micrograms of membrane protein [10].
• Triacsin C, a competitive inhibitor of both ACS1 and ACS4, inhibited ACS activity similarly in endoplasmic reticulum, MAM, and mitochondria, suggesting that a hitherto unidentified triacsin-sensitive ACS is present in mitochondria [13].
• METHODS: Human coronary endothelial cells were treated with triacsin-C, an inhibitor of long chain fatty acyl CoA synthetase, for 24 h [14].
• Gene array analysis revealed that both exogenous AA and triacsin C alter the expression of similar genes in HCT-116 cells [15].
• In order to determine whether newly synthesized acyl-CoAs are equally available for the synthesis of all glycerolipids and cholesterol esters, we incubated human fibroblasts with [14C]oleate, [3H]arachidonate or [3H]glycerol in the presence or absence of triacsin C, a fungal metabolite that is a competitive inhibitor of acyl-CoA synthetase [16].

Associations of WS 1228A with other chemical compounds

• Triacsin C, which inhibits the conversion of FFAs to long-chain acyl CoA (LC-CoA), enhanced basal FFA efflux as well as GLP-1-induced acidification and efflux of FFAs from the cell [17].
• Even though Faa1p, Faa4p, and RLACS are all able to activate imported myristate and palmitate in S. cerevisiae, the sensitivity of Faa4p and RLACS, but not Faa1p, to inhibition by triacsin C suggests that the rat liver enzyme is functionally more analogous to Faa4p than to Faa1p [18].
• In the presence of exogenous FFAs, the fatty acyl-CoA synthetase inhibitor triacsin C reduced secretion in response to glucose and nonfuel stimuli [19].
• The lipolysis of stored triacylglycerol was 5 times slower in lipid-loaded cells expressing perilipin A than in lipid-loaded control cells, when triacylglycerol synthesis was blocked with 6 microm triacsin C [20].
• Furthermore, addition of either the microsomal triglyceride transfer protein inhibitor or triacsin C, an inhibitor of acyl-CoA synthase, completely abrogated the oleate-dependent increase in apo(a) secretion [21].

Gene context of WS 1228A

• The long-chain acyl-CoA synthetase inhibitor triacsin C completely reversed fatty acid-induced ABCA1 destabilization, indicating that fatty acids need to be activated to their CoA derivatives to enhance ABCA1 degradation [22].
• Expression of ACSL5 suppressed Triacsin c-induced cytochrome c release and subsequent cell death (cell survival of Triacsin c-treated mock- versus ACSL5-transduced SF268 cells; means = 40% and 83%, respectively; difference = 43%, 95% CI = 39% to 47%; P<.001) [23].
• The cells were mock, transiently, or stably transfected with genes for Triacsin c-resistant ACSL5, dominant negative caspase-9, or apoptotic protease activating factor-1 knockdown [23].
• The ACS inhibitor triacsin C strongly inhibited ACS1 and ACS4, but not ACS5 [24].
• Addition of a proteasome inhibitor during triacsin C treatment abolished the ADRP decrease and accumulated polyubiquitinated ADRP [25].

Analytical, diagnostic and therapeutic context of WS 1228A

• Real-time polymerase chain reaction and immunoblotting demonstrated that mRNA and protein levels of one of the major AP-1 transcription factors, c-Jun, is markedly elevated by exogenous AA and triacsin C [15].
• The effect of triacsin C, a potent selective inhibitor of LCFA synthetase, on parasite growth was assessed in cell culture; complete inhibition of parasite growth at 2.5 ug/ml was obtained with little evidence of drug-associated cytotoxicity [26].
• Nude mice carrying NCI-H23 xenograft tumors (n = 10) were treated with Triacsin c or vehicle, and xenograft tumor growth was assessed [23].
• Finally, Triacsin c suppressed growth of xenograft tumors (relative tumor volume on day 21 of Triacsin c-treated versus untreated mice; means = 4.6 and 9.6, respectively; difference = 5.0, 95% CI = 2.1 to 7.9; P = .006) [23].

References