TOFA (RMI14514)
(Synonyms: 5-(十四烷基氧)-2-糠酸,RMI14514; MDL14514) 目录号 : GC32715
TOFA (RMI14514)是乙酰辅酶A羧化酶-α (ACCA)的变构抑制剂。.
Cas No.:54857-86-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
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Preparation Method |
cells (5000/well) were seeded in 96-well plates overnight and then exposed to TOFA at 1.0-50.0µg/ml for 72 h. |
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Reaction Conditions |
1.0-50.0µg/ml; 72 h |
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Applications |
TOFA showed strong cytotoxicity to all three human cancer cell lines, with an IC50 at approximately 5.0, 5.0, and 4.5µg/ml for NCI-H460, HCT-8, and HCT-15 cells. |
| Animal experiment [2]: | |
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Animal models |
Female athymic BALB/c nude mice |
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Preparation Method |
The cells were subcutaneously injected into both right and left flanks of each mouse. Twenty days later, mice treated with 50µl DMSO (control group) or treated with TOFA (50 mg/kg). The drugs were injected intraperitoneally daily for two weeks. |
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Dosage form |
50 mg/kg; i.p. |
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Applications |
The tumor growth rate was significantly inhibited by TOFA compared with the DMSO-treated control mice. |
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References: [1] Wang C , Xu C , Sun M ,et al.Acetyl-CoA Carboxylase-α Inhibitor TOFA Induces Human Cancer Cell Apoptosis[J].Biochemical and Biophysical Research Communications, 2009, 385(3):302-306. | |
TOFA (RMI14514) is a conformational inhibitor of acetyl-CoA carboxylase-α (ACCA). Within cells, TOFA is converted into TOFyl-CoA (5-tetradecyloxy-2-furoyl-CoA), which conformationally inhibits the rate-limiting enzyme ACCA in the fatty acid synthesis pathway[1]. TOFA prevents fatty acid synthesis and induces cancer cell death[2]. TOFA is a highly effective lipid-lowering agent[3].
In vitro, TOFA (0-50.0µg/ml) treatment of lung cancer cells (NCI-H460) and colon cancer cells (HCT-8 and HCT-15) for 72hours showed strong cytotoxicity, inducing apoptosis in a dose-dependent manner, with IC50 values of approximately 5.0µg/ml, 5.0µg/ml, and 4.5µg/ml, respectively[1]. Similarly, TOFA (0-50.0µg/ml) had IC50 values of approximately 26.1µg/mL for COC1 cells and 11.6µg/mL for COC1/DDP cells, blocking the cell cycle at the G0/G1 phase and inducing apoptosis[4]. TOFA (10µg/ml, 24h) treatment of PCa cell lines induced caspase activation and cell death[5]. TOFA (2-10 µg/ml) treatment of ACHN and 786-O cells for 48hours had IC50 values of approximately 6.06µg/ml and 5.36µg/ml, respectively[6].
In vivo, TOFA (50 mg/kg) administered intraperitoneally daily for two weeks in a xenograft mouse model of human ovarian cancer significantly inhibited tumor growth rate, with no toxicity observed in the heart, liver, spleen, lungs, kidneys, and intestinal tissues[4].
References:
[1] Wang C , Xu C , Sun M ,et al.Acetyl-CoA Carboxylase-α Inhibitor TOFA Induces Human Cancer Cell Apoptosis[J].Biochemical and Biophysical Research Communications, 2009, 385(3):302-306.
[2] Tan W , Zhong Z , Wang S ,et al.Berberine Regulated Lipid Metabolism in the Presence of C75, Compound C, and TOFA in Breast Cancer Cell Line MCF-7[J].Evidence-based complementary and alternative medicine: eCAM, 2015(10).
[3] Leyuan, ChenYuqing, DuanHuiqiang, et al. Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors[J].Expert opinion on investigational drugs, 2019, 28(7a12).
[4] Li S, Qiu L, Wu B et al. TOFA suppresses ovarian cancer cell growth in vitro and in vivo. Mol Med Rep. 2013 Aug;8(2):373-8.
[5]Guseva NV, et al. 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. 2011 Jul 1;12(1):80-5.
[6]Dejiao H , Xuan S , Hongxia Y ,et al.TOFA induces cell cycle arrest and apoptosis in ACHN and 786-O cells through inhibiting PI3K/Akt/mTOR pathway[J].Journal of Cancer, 2018, 9(15):2734-2742.
TOFA (RMI14514)是乙酰辅酶A羧化酶-α (ACCA)的变构抑制剂。TOFA在细胞内转化为TOFyl-CoA (5-tetradecyloxy-2-furoyl-CoA),对脂肪酸合成途径的限速酶ACCA具有变构抑制作用[1]。TOFA阻止脂肪酸合成,并诱导癌细胞死亡[2]。TOFA是一种非常有效的降血脂剂[3]。
在体外,TOFA(0-50.0µg/ml)处理肺癌细胞(NCI-H460)和结肠癌细胞(HCT-8和HCT-15)72小时,均表现出较强的细胞毒性,以剂量依赖性方式诱导细胞凋亡,IC50分别约为5.0µg/ml、5.0µg/ml、4.5µg/ml[1]。类似地,TOFA (0-50.0µg/ml)对 COC1 和 COC1/DDP 细胞的IC50值分别约为26.1µg/mL和11.6 µg/mL,可将细胞周期阻滞在G0/G1期并诱导细胞凋亡[4]。TOFA(10µg/ml,24h)处理PCa细胞系,可以诱导半胱天冬酶活化和细胞死亡[5]。TOFA(2-10 µg/ml)对ACHN和786-O细胞处理48h,IC50分别约为6.06µg/ml和5.36 µg/ml[6]。
在体内,TOFA(50 mg/kg)持续两周每天腹腔注射治疗人卵巢癌细胞异种移植小鼠,可显著抑制肿瘤生长速率,在心脏、肝脏、脾脏、肺、肾和肠道组织中未观察到毒性[4]。
| Cas No. | 54857-86-2 | SDF | |
| 别名 | 5-(十四烷基氧)-2-糠酸,RMI14514; MDL14514 | ||
| Canonical SMILES | O=C(C1=CC=C(OCCCCCCCCCCCCCC)O1)O | ||
| 分子式 | C19H32O4 | 分子量 | 324.45 |
| 溶解度 | DMSO : ≥ 34 mg/mL (104.79 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0821 mL | 15.4107 mL | 30.8214 mL |
| 5 mM | 0.6164 mL | 3.0821 mL | 6.1643 mL |
| 10 mM | 0.3082 mL | 1.5411 mL | 3.0821 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Efficacy and safety of tofacitinib versus baricitinib in patients with rheumatoid arthritis in real clinical practice: analyses with propensity score-based inverse probability of treatment weighting
Ann Rheum Dis 2021 Sep;80(9):1130-1136.PMID:33827788DOI:10.1136/annrheumdis-2020-219699.
Objectives: The differences of efficacy between each Janus kinase (JAK) inhibitors have not been clarified in the patients with rheumatoid arthritis (RA) in clinical practice. Here, we compared the efficacy between tofacitinib (TOFA) and baricitinib (BARI) in clinical practice. Methods: The efficacy of TOFA (n=156) in patients with RA was compared with BARI (n=138). Selection bias was reduced to a minimum using propensity score-based inverse probability of treatment weighting (IPTW). The Clinical Disease Activity Index (CDAI) trajectory for patients who started TOFA or BARI was analysed using growth mixture modelling (GMM). Results: No significant difference was observed in patient characteristics between the TOFA and BARI groups in after adjustment by propensity score-based IPTW. The BARI group had a significantly higher rate of CDAI remission at week 24 after the introduction of JAK inhibitors than the TOFA group. The treatment-resistant group defined by GMM, comprising patients who did not achieve low disease activity at week 24, was more likely to include those who had received many biological disease-modifying antirheumatic drugs (bDMARDs) before the introduction of JAK inhibitors and those who received TOFA. Among patients with RA who received TOFA, those who had received ≥4 bDMARDs before the introduction of TOFA were more likely to be classified into the treatment-resistant group. Conclusions: BARI showed a similar safety profile and better clinical outcome when compared with TOFA after reduction to a minimum of selection bias. However, these were observed in a small population. Accordingly, further investigation is required in an accurately powered head-to-head trial.
TOFA induces cell cycle arrest and apoptosis in ACHN and 786-O cells through inhibiting PI3K/Akt/mTOR pathway
J Cancer 2018 Jun 23;9(15):2734-2742.PMID:30087714DOI:10.7150/jca.26374.
Cancer cells usually have a high requirement for fatty acids in order to meet the rapid proliferation and metabolism. Acetyl-CoA carboxylase-α(ACCA) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA and has been a rate-limiting enzyme in the synthesis of long chain fatty acid and cellular energy storage. 5-tetradecyloxy-2-furoic acid (TOFA) is well known as an allosteric inhibitor of ACCA. In this study, we examined the functions of TOFA in human renal cell carcinoma (RCC) cell lines ACHN and 786-O. According to the results, TOFA inhibited ACHN and 786-O cell growth in a concentration and time dependent manner. The IC50 values of ACHN and 786-O cells were 6.06 and 5.36 µg/ml by the treatment of TOFA for 48 h, respectively. Flow cytometry analysis showed that TOFA markedly arrest cell cycle at G2/M phase and lead to cell apoptosis. In addition, Western blot results revealed that TOFA decreased the phosphorylation of proteinkinaseB(Akt), Mammalian target of rapamycin (mTOR) and p70 ribosomal protein S6 kinase (p70S6K). What's more, specific phosphoinositide 3-kinases (PI3K) phosphorylation inhibitor LY294002 potentiated TOFA anti-cancer activity. These results suggested that TOFA induces growth restraint and apoptosis via inhibiting the PI3K/Akt/mTOR pathway and TOFA may be a novel therapeutic strategy for RCC treatment.
[Effects of TOFA on growth of Eca109 and KYSE-450 cells in human esophageal squamous cell carcinoma]
Zhongguo Ying Yong Sheng Li Xue Za Zhi 2022 Jul;38(4):317-321.PMID:36414554DOI:10.12047/j.cjap.6236.2022.060.
Objective: To investigate the effects of 5-tetradecanoxy 2-furanic acid (TOFA) on cell proliferation, cell cycle and apoptosis of esophageal squamous cell carcinoma (ESCC) cells. Methods: Eca-109 cells and KYSE-450 cells were divided into control group (DMSO) and experimental group (TOFA), respectively. The cells (4×103 cells/100 μl) were inoculated into 96-well plates with 5 multiple wells at each concentration. After 24 h culture, cells were treated with DMSO or different concentrations (1, 3, 5, 10 μg/ ml) of TOFA for 24, 48 and 72 h. Cell proliferation was detected by MTT, cell cycle and apoptosis were detected by flow cytometry, the expression levels of p21 and Cleaved caspase-3 and modification levels of p-Akt, p-mTOR and p-4EBP1 were detected by Western blot, and intracellular free fatty acids were detected by special kits. Results: MTT results showed that TOFA inhibited the proliferation of Eca109 and KYSE-450 cells in a concentration and time dependent manner (all P<0.05), with IC50 of 4.65 μg/ml and 3.93 μg/ml for 48 h, respectively. Flow cytometry results showed that compared with DMSO group, the percentage of cells in G2/M phase was increased and the apoptosis rate was increased in the experimental group. Western blotting results showed that compared with DMSO group, p21 and Cleaved caspase-3 protein expression levels were up-regulated, and p-AKT, p-mTOR and p-4EBP1 protein expression levels were down-regulated (all P<0.05). Conclusion: TOFA inhibits the proliferation, blocks the cycle progression and promotes apoptosis of ESCC, the mechanism may be related to the AKT/mTOR/4EBP1 signaling pathway.
TOFA suppresses ovarian cancer cell growth in vitro and in vivo
Mol Med Rep 2013 Aug;8(2):373-8.PMID:23732836DOI:10.3892/mmr.2013.1505.
A characteristic feature of cancer cells is the activation of de novo fatty acid synthesis. Acetyl‑CoA carboxylase (ACC) is a key enzyme in fatty acid synthesis, accelerating the reaction that carboxylates cytosolic acetyl‑CoA to form malonyl‑CoA. ACC is highly expressed in several types of human cancer and is important in breast and prostate cancer cell growth. The aim of the present study was to investigate the effects of 5‑tetradecyloxy‑2‑furoic acid (TOFA), an allosteric inhibitor of ACC, on the proliferation and cell cycle progression of the ovarian cancer cell lines COC1 and COC1/DDP. TOFA was found to be cytotoxic to COC1 and COC1/DDP cells with a 50% inhibitory concentration (IC50) of ~26.1 and 11.6 µg/ml, respectively. TOFA 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. The expression of the cell cycle regulating proteins cyclin D1 and cyclin-dependent kinase (CDK) 4, as well as the expression of the apoptosis‑related proteins caspase‑3 and Bcl‑2, were detected by western blot analysis. Cyclin D1, CDK4 and Bcl‑2 protein expression was inhibited by TOFA, while caspase‑3 was cleaved and activated. To the best of our knowledge, the present study demonstrated for the first time that TOFA inhibits COC1/DDP cell growth in ovarian tumor mouse xenografts. By inhibiting ACC, TOFA may be a promising small molecule agent for ovarian cancer therapy.
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 2011 Jul 1;12(1):80-5.PMID:21525791DOI:10.4161/cbt.12.1.15721.
A key player in prostate cancer development and progression is the androgen receptor (AR). Tumor-associated lipogenesis can protect cancer cells from carcinogenic- and therapeutic-associated treatments. Increased synthesis of fatty acids and cholesterol is regulated by androgens through induction of several genes in androgen-responsive cancer cells. Acetyl-CoA-carboxylase-α (ACCA) is a key enzyme in the regulation of fatty acids synthesis. Here we show that AR binds in vivo to intron regions of human ACCA gene. We also show that the level of ACCA protein in LNCaP depends on AR expression and that DHT treatment increases ACCA expression and fatty acid synthesis. Inhibition of ACCA by TOFA (5-tetradecyl-oxy-2-furoic acid) decreases fatty acid synthesis and induces caspase activation and cell death in most PCa cell lines. Our data suggest that TOFA can kill cells via the mitochondrial pathway since we found cytochrome c release after TOFA treatment in androgen sensitive cell lines. The results also imply that the pro-apoptotic effect of TOFA may be mediated via a decrease of neuropilin-1(NRP1) and Mcl-1expression. We have previously reported that Mcl-1 is under AR regulation and plays an important role in resistance to drug-induced apoptosis in prostate cancer cells, and NRP1 is known to regulate Mcl-1 expression. Here, we show for the first time that NRP1 expression is under AR control. Taken together, our data suggest that TOFA is a potent cell death inducing agent in prostate cancer cells.