Molecular Oncology (NEOMA), School of Medicine, University of Girona and Girona Institute for Biomedical Research (IDIBGi), 17071, Girona, Spain.
BMC Cancer. 2012 Jul 6;12:280. doi: 10.1186/1471-2407-12-280.
Fatty acid synthase (FASN) is overexpressed and hyperactivated in several human carcinomas, including lung cancer. We characterize and compare the anti-cancer effects of the FASN inhibitors C75 and (-)-epigallocatechin-3-gallate (EGCG) in a lung cancer model.
We evaluated in vitro the effects of C75 and EGCG on fatty acid metabolism (FASN and CPT enzymes), cellular proliferation, apoptosis and cell signaling (EGFR, ERK1/2, AKT and mTOR) in human A549 lung carcinoma cells. In vivo, we evaluated their anti-tumour activity and their effect on body weight in a mice model of human adenocarcinoma xenograft.
C75 and EGCG had comparable effects in blocking FASN activity (96,9% and 89,3% of inhibition, respectively). In contrast, EGCG had either no significant effect in CPT activity, the rate-limiting enzyme of fatty acid β-oxidation, while C75 stimulated CPT up to 130%. Treating lung cancer cells with EGCG or C75 induced apoptosis and affected EGFR-signaling. While EGCG abolished p-EGFR, p-AKT, p-ERK1/2 and p-mTOR, C75 was less active in decreasing the levels of EGFR and p-AKT. In vivo, EGCG and C75 blocked the growth of lung cancer xenografts but C75 treatment, not EGCG, caused a marked animal weight loss.
In lung cancer, inhibition of FASN using EGCG can be achieved without parallel stimulation of fatty acid oxidation and this effect is related mainly to EGFR signaling pathway. EGCG reduce the growth of adenocarcinoma human lung cancer xenografts without inducing body weight loss. Taken together, EGCG may be a candidate for future pre-clinical development.
脂肪酸合酶（FASN）在包括肺癌在内的几种人类癌瘤中过度表达和过度激活。我们对 FASN 抑制剂 C75 和（-）-表没食子儿茶素-3-没食子酸酯（EGCG）在肺癌模型中的抗癌作用进行了表征和比较。
我们评估了 C75 和 EGCG 在体外对脂肪酸代谢（FASN 和 CPT 酶）、细胞增殖、凋亡和细胞信号（EGFR、ERK1/2、AKT 和 mTOR）的影响，在人类 A549 肺癌细胞中。在体内，我们评估了它们在人腺癌异种移植小鼠模型中的抗肿瘤活性及其对体重的影响。
C75 和 EGCG 对 FASN 活性的抑制作用相当（分别为 96.9%和 89.3%）。相比之下，EGCG 对 CPT 活性没有明显影响，CPT 是脂肪酸β氧化的限速酶，而 C75 则将 CPT 刺激至 130%。用 EGCG 或 C75 处理肺癌细胞可诱导细胞凋亡并影响 EGFR 信号。虽然 EGCG 消除了 p-EGFR、p-AKT、p-ERK1/2 和 p-mTOR，但 C75 在降低 EGFR 和 p-AKT 水平方面的活性较低。在体内，EGCG 和 C75 阻断了肺癌异种移植瘤的生长，但 C75 治疗而非 EGCG 导致动物体重明显下降。
在肺癌中，使用 EGCG 抑制 FASN 可以在不平行刺激脂肪酸氧化的情况下实现，这种作用主要与 EGFR 信号通路有关。EGCG 可减少人肺癌腺癌异种移植瘤的生长而不引起体重减轻。总之，EGCG 可能是未来临床前开发的候选药物。
