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. 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 IC50s at approximately 5.0, 5.0, and 4.5 μg/ml, respectively. TOFA at 1.0-20.0 μg/ml effectively blocked fatty acid synthesis and induced cell death in a dose-dependent manner[2]. TOFA was also cytotoxic to COC1 and COC1/DDP cells with IC50s of ~26.1 and 11.6 µg/ml, respectively. It inhibited the proliferation of the cancer cells examined in a time and dose dependent manner, arrested the cells in the G0/G1 cell cycle phase and induced apoptosis. In a human ovarian cancer mouse xenograft model, tumor growth rate was significantly inhibited by TOFA compared with the DMSO-treated control mice (1649 ± 356.3 vs. 5128 ± 390.4 mm3)[3].
TOFA 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Daudi cells
0.3, 1, 3, 10 μg/mL
24-48 hours
Inhibition of lipogenesis leads to apoptosis
Cancer Metab. 2021 Aug 16;9(1):31.
P493-6 cells
0.3, 1, 3, 10 μg/mL
24-48 hours
Inhibition of lipogenesis leads to apoptosis
Cancer Metab. 2021 Aug 16;9(1):31.
4188 cells
0.3, 1, 3, 10 μg/mL
24-48 hours
Inhibition of lipogenesis leads to apoptosis
Cancer Metab. 2021 Aug 16;9(1):31.
CD8+ T cells
1 µM
5 days
Inhibited CD8+ T cell proliferation
J Transl Med. 2023 Jul 4;21(1):434.
CD8+ T cells
1 µM
Decreased IFN-γ, granzyme B, perforin levels
J Transl Med. 2023 Jul 4;21(1):434.
CD8+ T cells
1 µM
24 hours
Reduced CD69 membrane expression
J Transl Med. 2023 Jul 4;21(1):434.
K562 cells
0.3, 1, 3, 10 μg/mL
24-48 hours
Inhibition of lipogenesis leads to apoptosis
Cancer Metab. 2021 Aug 16;9(1):31.
Ramos cells
0.3, 1, 3, 10 μg/mL
24-48 hours
Inhibition of lipogenesis leads to apoptosis
Cancer Metab. 2021 Aug 16;9(1):31.
BSC40 cells
154 µM
16 hours
To evaluate the impact of TOFA on vaccinia virus yield. Results showed TOFA significantly inhibited viral yield by 95-fold, with partial rescue (8-fold) provided by exogenous palmitate.
PLoS Pathog. 2014 Mar 20;10(3):e1004021.
PBMCs
0.08–2 µM
2 days
TOFA reversed Th17/Treg imbalance and inhibited IL-2–induced STAT1/3 phosphorylation.
JCI Insight. 2022 Dec 8;7(23):e162335.
HEK-293T cells
5 µM
23 hours
Combination of TOFA with pimozide significantly enhanced antiviral effects.
Nat Commun. 2016 May 12;7:11320.
PBMCs
0.08–10 µM
24 hours
TOFA cytotoxicity was assessed using a CCK8 assay, and we found no substantial cytotoxicity of the drug when concentrations less than 10 μM were used.
JCI Insight. 2022 Dec 8;7(23):e162335.
CCRF-CEM cells
0.3, 1, 3, 10 μg/mL
24-48 hours
Inhibition of lipogenesis leads to apoptosis
Cancer Metab. 2021 Aug 16;9(1):31.
Human bone marrow-derived stromal cells (hBMSCs)
200, 400, or 800 nM
3 days
Under non-inflammatory conditions, Tofa treatment significantly decreased the gene expression of Runx2 and Dlx5 (p <0.05) and increased the gene expression of PPAR g2, C/EBPa, and Perilipin 1 (p <0.05). Under inflammatory conditions, Tofa limited the negative effect of TNF a on BMAd differentiation (p <0.05).
Front Endocrinol (Lausanne). 2022 Jul 6;13:881699.
Human naive CD4 T cells
10 µM
4 days
TOFA significantly increased IL-9 production by inhibiting ACC1 and reduced the proportion of Foxp3+ cells. Exogenous oleic acid restored IL-9 levels in TOFA-treated cells.
Front Immunol. 2024 Dec 23;15:1509408.
Normal human epidermal keratinocytes (NHEKs)
1 µM
48 hours
Inhibited production and secretion of CXCL9 and CXCL10
J Transl Med. 2023 Jul 4;21(1):434.
U2OS cells
10 µM
48 hours
TOFA inhibited lipid accumulation, promoted early slippage, reduced cellular stress and enhanced survival of antimitotic-treated cells
Investigate the effects of TOFA on gene expression in RA-FLS, showing that TOFA primarily downregulated gene expression, affecting interferon signaling pathways.
Arthritis Res Ther. 2024 Oct 11;26(1):178.
U87 cells
39.98 µM (IC50)
5 days
TOFA showed an IC50 value of 39.98 µM for U87 cells, indicating inhibitory effects on TMZ-sensitive cells.
Acta Pharmacol Sin. 2023 Mar;44(3):670-679.
U87R cells
7.51 µM (IC50)
5 days
TOFA showed an IC50 value of 7.51 µM for U87R cells, indicating inhibitory effects on TMZ-resistant cells.
Acta Pharmacol Sin. 2023 Mar;44(3):670-679.
HeLa cells
25 µM
7 hours
TOFA significantly reduced viral RNA synthesis and release, with no significant effect on cell viability.
Nat Commun. 2016 May 12;7:11320.
TOFA 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Sprague-Dawley rats
Cecal ligation and perforation (CLP)-induced sepsis model
Intragastric administration
1 mg/kg, 3 mg/kg, 10 mg/kg
Every 6 hours for 7 days
To evaluate the effect of TOFA on the survival rate of septic rats and its role in acute lung injury. The results showed that TOFA (10 mg/kg) significantly improved the survival rate of septic rats and reduced lung histopathological damage and inflammatory factor expression
J Inflamm (Lond). 2023 Feb 3;20(1):5
New Zealand white rabbits
Experimental rheumatoid arthritis (e-RA)
Oral
10 mg/kg
Once daily for two weeks
To evaluate the effect of JAK inhibitors on muscle remodeling in an experimental RA model. TOFA significantly improved muscle mass and structural parameters, reduced the expression of muscle atrophy-related genes, and increased creatine kinase (CK) levels in muscle.
Int J Mol Sci. 2023 Aug 24;24(17):13181
New Zealand white rabbits
Antigen-induced arthritis model
Oral gavage
10 mg/kg
Once daily for 2 weeks
To investigate the early effects of TOFA on intra-joint JAK/STAT-dependent signaling during flare-up reactions in arthritis. Results showed that TOFA partially improved synovitis, reduced levels of pSTAT1 and SOCS1, but had no effect on pSTAT3 or SOCS3.
J Inflamm (Lond). 2019 Jan 29;16:2
C57BL/6 mice
Adult Mice footpad injection model
Intraperitoneal injection
25 mg/kg
Pretreated for at least 3 days before infection and assessed 18 h p.i.
TOFA significantly reduced CHIKV replication.
Nat Commun. 2016 May 12;7:11320.
C57BL6/J mice
GPx1/2-DKO Mice model
Oral
30 mg/kg
Once daily for 6 or 13 days
To evaluate the efficacy of TOFA on very-early-onset ileocolitis in GPx1/2-DKO mice. Results showed that TOFA significantly inhibited crypt apoptosis and increased crypt density, but did not affect Mice growth.
Life Sci. 2019 Dec 15;239:116884
C57BL/6 mice
Vitiligo Mice model
Intraperitoneal injection
5 mg/kg
Once every other day for five weeks
Alleviated the extent of depigmentation and reduced CD8+ T cell skin infiltration
J Transl Med. 2023 Jul 4;21(1):434.
Mice
NSG mice
Intraperitoneal injection
5.5 μg/ml
4 days
Inhibition of lipogenesis delays tumor progression
Cancer Metab. 2021 Aug 16;9(1):31.
Lewis rats
Fisher-to-Lewis rat model of kidney transplantation
Oral (mixed with food)
50 mg/kg and 100 mg/kg
From the third week post-transplantation until the end of the study (12 weeks)
TOFA prolonged graft survival, preserved tubular and glomerular structures and reduced humoral damage characterized by C4d deposition. TOFA was able to reduce donor-specific antibodies. In addition, T and natural killer (NK) cell graft infiltration was reduced in TOFA-treated rats.
搜索
