Selective inhibition of fatty acid synthase for lung cancer treatment
Selective inhibition of fatty acid synthase for lung cancer treatment
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DOI：
10.1158/1078-0432.ccr-07-1186
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发表时间：
2007-12-01
影响因子：
11.5
通讯作者：
Gabrielson, Edward
中科院分区：
文献类型：
--
作者：
Orita, Hajime;Coulter, Jonathan;Gabrielson, Edward
目的：脂肪酸合成酶(Fas)在许多人类癌症中过表达，被认为是一个有希望的治疗靶点。然而，前几代Fas抑制剂的体外使用一直受到严重但可逆的治疗动物厌食症的限制，这被认为与这些药物平行刺激脂肪酸氧化有关。本研究在临床前肺癌模型中研究了C93对Fas的药理抑制作用，C93是一种设计合理的分子，可以在不影响脂肪酸氧化的情况下抑制Fas的活性。实验设计：在培养的非小细胞肺癌(NSCLC)细胞中，评估C93对Fas和脂肪酸氧化的活性。口服或ip该化合物的抗肿瘤活性。在南卡罗来纳州进行了评估。结果：我们的实验证实C93有效地抑制肺癌细胞中的Fas，而不刺激脂肪酸氧化。更重要的是，C93显著抑制了这两种细菌的生长。和来自人NSCLC细胞系的原位移植瘤，而不会引起厌食和体重减轻。结论：在没有平行的脂肪酸氧化刺激的情况下，可以实现对Fas的抑制，并且可以在没有厌食和体重下降的情况下抑制体内肿瘤的生长。因此，这一治疗策略有望用于癌症的临床治疗，包括非小细胞肺癌，非小细胞肺癌是美国和欧洲癌症死亡的主要原因。
Purpose: Fatty acid synthase (FAS) is overexpressed in many human cancers and is considered to be a promising target for therapy. However, in vitro use of previous generations of FAS inhibitors has been limited by severe, but reversible, anorexia in treated animals, which is thought to be related to a parallel stimulation of fatty acid oxidation by these agents. This study investigated pharmacologic inhibition of FAS using C93, a rationally designed molecule that inhibits FAS activity without affecting fatty acid oxidation in preclinical models of lung cancer.Experimental Design: Activity of C93 on FAS and fatty acid oxidation was evaluated in cultured non -small cell lung cancer (NSCLC) cells. Antineoplastic activity of the compound, given orally or by i.p. injection, was evaluated in s.c. and orthotopic NSCLC xenografts.Results: Our experiments confirm that C93 effectively inhibits FAS without stimulating fatty acid oxidation in lung cancer cells. More importantly, C93 significantly inhibits the growth of both s.c. and orthotopic xenograft tumors from human NSCLC cell lines without causing anorexia and weight loss in the treated animals.Conclusions: We conclude that inhibition of FAS can be achieved without parallel stimulation of fatty acid oxidation and that inhibition of tumor growth in vivo can be achieved without anorexia and weight loss. Thus, this therapeutic strategy holds promise for clinical treatment of cancers, including non -small cell lung cancer, the leading cause of cancer mortality in the United States and Europe.