Department of Clinical Pharmacology, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.
Department of Continuing Education and Science and Technology Service, China Anti-Cancer Association, Tianjin, China.
Lipids Health Dis. 2023 Aug 23;22(1):134. doi: 10.1186/s12944-023-01907-y.
Anlotinib has demonstrated encouraging clinical outcomes in the treatment of lung cancer, soft tissue sarcoma and thyroid carcinoma. Several clinical studies have shown a relationship between anlotinib treatment and the occurrence of hyperlipidemia. The fundamental mechanisms, however, are still largely unclear. Here, the effect of anlotinib on lipid metabolism in an animal model and human cancer cells was evaluated and the role of lipid metabolism in the antitumor efficacy of anlotinib was investigated.
The C57BL/6 J mouse model as well as A549 and H460 human lung cancer cell lines were used to examine the impact of anlotinib on lipid metabolism both in vivo and in vitro. Levels of triglycerides, high-density lipoprotein, low-density lipoprotein (LDL), and total cholesterol in serum or cell samples were determined using assay kits. The expression levels of crucial genes and proteins involved in lipid metabolism were measured by quantitative RT-PCR and Western blotting. Furthermore, exogenous LDL and knockdown of low-density lipoprotein receptor (LDLR) were used in H460 cells to investigate the relevance of lipid metabolism in the anticancer efficacy of anlotinib.
Anlotinib caused hyperlipidemia in C57BL/6 J mice, possibly by downregulating hepatic LDLR-mediated uptake of LDL cholesterol. AMP-activated protein kinase and mammalian target of rapamycin inhibition may also be involved. Additionally, anlotinib enhanced sterol response element binding protein 1/2 nuclear accumulation as well as upregulated LDLR expression in A549 and H460 cells, which may be attributable to intracellular lipid accumulation. Knockdown of LDLR reduced intracellular cholesterol content, but interestingly, anlotinib significantly improved intracellular cholesterol accumulation in LDLR-knockdown cells. Both exogenous LDL and LDLR knockdown decreased the sensitivity of cells to anlotinib.
Anlotinib modulates host lipid metabolism through multiple pathways. Anlotinib also exerts a significant impact on lipid metabolism in cancer cells by regulating key transcription factors and metabolic enzymes. In addition, these findings suggest lipid metabolism is implicated in anlotinib sensitivity.
安罗替尼在治疗肺癌、软组织肉瘤和甲状腺癌方面显示出令人鼓舞的临床疗效。几项临床研究表明，安罗替尼治疗与高脂血症的发生之间存在关联。然而，其基本机制在很大程度上仍不清楚。本研究评估了安罗替尼在动物模型和人类癌细胞中的脂质代谢作用，并探讨了脂质代谢在安罗替尼抗肿瘤疗效中的作用。
采用 C57BL/6J 小鼠模型以及 A549 和 H460 人肺癌细胞系，研究安罗替尼在体内和体外对脂质代谢的影响。采用试剂盒检测血清或细胞样本中甘油三酯、高密度脂蛋白、低密度脂蛋白（LDL）和总胆固醇的水平。采用定量 RT-PCR 和 Western blot 检测脂质代谢关键基因和蛋白的表达水平。此外，在 H460 细胞中外源性 LDL 和低密度脂蛋白受体（LDLR）敲低，以研究脂质代谢在安罗替尼抗癌疗效中的相关性。
安罗替尼导致 C57BL/6J 小鼠发生高脂血症，可能是通过下调肝 LDLR 介导的 LDL 胆固醇摄取所致。此外，AMP 激活的蛋白激酶和哺乳动物雷帕霉素靶蛋白的抑制也可能参与其中。此外，安罗替尼增强了 A549 和 H460 细胞中固醇反应元件结合蛋白 1/2 的核积累，并上调了 LDLR 的表达，这可能归因于细胞内脂质的积累。LDLR 敲低降低了细胞内胆固醇含量，但有趣的是，安罗替尼显著改善了 LDLR 敲低细胞内胆固醇的积累。外源性 LDL 和 LDLR 敲低均降低了细胞对安罗替尼的敏感性。
安罗替尼通过多种途径调节宿主脂质代谢。安罗替尼还通过调节关键转录因子和代谢酶对癌细胞的脂质代谢产生显著影响。此外，这些发现表明脂质代谢与安罗替尼的敏感性有关。
