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Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2~+ Breast Cancer

机译:Fasnall,一种选择性的FASN抑制剂,在HER2〜+乳腺癌的MMTV-Neu模型中显示出强大的抗肿瘤活性

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摘要

Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids. We also showed that the increase in ceramide levels contributes to some extent in the mediation of apoptosis. Consistent with this mechanism of action, Fasnall showed potent anti-tumor activity in the MMTV-Neu model of HER2~+ breast cancer, particularly when combined with carboplatin.
机译:许多肿瘤依赖于从头合成脂肪酸来维持细胞生长。脂肪酸合酶(FASN)催化该途径的最终合成步骤,其上调与肿瘤侵袭性相关。急性或慢性抑制必需酶(例如FASN)的后果和适应性反应尚不完全清楚。在本文中,我们鉴定出Fasnall,一种通过其辅助因子结合位点选择性靶向FASN的噻吩并嘧啶。 Fasnall进行的全球脂质组学研究表明,细胞脂质谱发生了深刻变化,神经酰胺,二酰基甘油和不饱和脂肪酸急剧增加,外源性棕榈酸酯摄取增加,而后者更多地偏向中性脂质形成而不是磷脂。我们还表明,神经酰胺水平的提高在一定程度上有助于细胞凋亡的介导。与此作用机制一致,Fasnall在HER2 ++乳腺癌的MMTV-Neu模型中表现出有效的抗肿瘤活性,尤其是与卡铂联合使用时。

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