Description
TOFA (54857-86-2) interferes with fatty acid synthase via inhibition of acetyl Co-A carboxylase (ACC1).1 Induces apoptosis in a variety of tumor cell lines.2,3 Stimulates neurite outgrowth and neuronal differentiation in rat pheochromocytoma cells.4 TOFA impairs glucose-stimulated insulin secretion after chronic treatment.5
Uses
TOFA has been used as a lipid biosynthesis inhibitor in mesenchymal stromal cells (MSCs), human pluripotent stem cells., an acetyl-CoA carboxylase 1 inhibitor in murine adipocyte cell lines., a lipolysis inhibitor in cancer stem cells (CSCs).
Definition
ChEBI: A member of the class of furans that is 2-furoic acid in which the hydrogen at position 5 is replaced by a tetradecyloxy group.
Biochem/physiol Actions
5-(Tetradecyloxy)-2-furoic acid (TOFA) elicits hypolipidemicfunctionality by favoring fatty acid breakdown and at the same time preventing biosynthesis. It induces apoptosis in pancreatic cancer cells and favors tumor suppression.
in vivo
TOFA inhibits COC1/DDP cell growth in ovarian tumor mouse xenografts. The tumor growth rate is signifi cantly inhibited by TOFA compared with the DMSO treated control mice (1649±356.3 vs. 5128±390.4 mm3. No toxicity is observed in the heart, liver, spleen, lung, kidney and intestinal tissues. By inhibiting ACC, TOFA may be a promising small molecule agent for ovarian cancer therapy[2].
Background
The small-molecule TOFA is an allosteric inhibitor of acetyl-CoA carboxylase-α, which catalyzes carboxylation of acetyl-CoA to malonyl-CoA in cells. It is the key enzyme in the biosynthesis and oxidation of fatty acids. Conversion of TOFA to an acetyl-CoA analog that cannot be further metabolized to malonyl-CoA creates an allosteric inhibitor of ACC. Because many cancer cells require fatty acids for high metabolic needs and rapid proliferation, the reduction of ACC activity is a common target in limiting cancer cell growth. TOFA treatment of lung cancer and colon carcinoma cells blocked fatty acid synthesis, and increased fatty acid oxidation and ketogenesis, inducing apoptosis and cell death. Exposure of human pancreatic cancer cells to TOFA resulted in fatty acid depletion, increased caspase-3 activity, and induced cell death. TOFA treatment of human renal cell carcinoma inhibited cell growth and arrested cell cycle at G2/M phase, leading to apoptosis.
References
References/Citations:
(1)Halvorson et al. (1984), Inhibition of fatty acid synthesis in isolated adipocytes by 5-tetradecyloxy)-2-furoic acid; Lipids, 19 851
(2) Guseva et al. (2011), TOFA (5-tetradecyl-oxy-2-furoic acid) reduces fatty acid synthesis, inhibits expression of AR, neuropilin-1 and Mcl-1 and kills prostate cancer cells independent of p53 status; Cancer Biol. Ther., 12 80
(3) Zhou et al. (2003), Fatty acid synthesis inhibition triggers apoptosis during S phase in human cancer cells; Cancer Res., 63 7330
(4) Schmidt et al. (1999), Transcription control and neuronal differentiation by agents that activate the LXR nuclear receptor family; Mol. Cell. Endocrinol., 155 51
(5) Ronnebaum et al. (2008), Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism; J. Biol. Chem., 283 14248
