Acetyl-CoA carboxylase-alpha inhibitor TOFA induces human cancer cell apoptosis.
Acetyl-CoA carboxylase-alpha (ACCA) is a rate-limiting enzyme in long chain fatty acid synthesis, playing a critical role in cellular energy storage and lipid synthesis. ACCA is upregulated in multiple types of human cancers and small interfering RNA-mediated ACCA silencing in human breast and prostate cancer cells results in oxidative stress and apoptosis. This study reports for the first time that TOFA (5-tetradecyloxy-2-furoic acid), an allosteric inhibitor of ACCA, is cytotoxic to lung cancer cells NCI-H460 and colon carcinoma cells HCT-8 and HCT-15, with an IC(50) at approximately 5.0, 5.0, and 4.5 microg/ml, respectively. TOFA at 1.0-20.0 microg/ml effectively blocked fatty acid synthesis and induced cell death in a dose-dependent manner. The cell death was characterized with PARP cleavage, DNA fragmentation, and annexin-V staining, all of which are the features of the apoptosis. Supplementing simultaneously the cells with palmitic acids (100 microM), the end-products of the fatty acid synthesis pathway, prevented the apoptosis induced by TOFA. Taken together, these data suggest that TOFA is a potent cytotoxic agent to lung and colon cancer cells, inducing apoptosis through disturbing their fatty acid synthesis.
Wang
Chun
C
School of Pharmaceutical Sciences, Central South University, Changsha 410083, China.
Xu
Canxin
C
Sun
Mingwei
M
Luo
Dixian
D
Liao
Duan-Fang
DF
Cao
Deliang
D
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D003603:Cytotoxins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D019308:Palmitic Acid / Q000494:pharmacology
D003603:Cytotoxins; D004791:Enzyme Inhibitors; D005663:Furans; D019308:Palmitic Acid; C014289:5-(tetradecyloxy)-2-furancarboxylic acid; D000103:Acetyl-CoA Carboxylase