TOFA (RMI14514)

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]。