Altered phospholipid transfer protein gene expression and serum lipid profile by topotecan.
Altered phospholipid transfer protein gene expression and serum lipid profile by topotecan.
复制标题
拓扑替康改变磷脂转移蛋白基因表达和血清脂质谱。
DOI：
10.1016/j.bcp.2010.04.015
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发表时间：
2010
影响因子：
5.8
通讯作者：
Chin,Khew-Voon
中科院分区：
文献类型：
--
作者：
Saunders,RudelA;Fujii,Kazuyuki;Alabanza,Leah;Ravatn,Roald;Kita,Tsunekazu;Kudoh,Kazuya;Oka,Masahiro;Chin,Khew-Voon
喜树碱 (CPT) 及其结构类似物（包括拓扑替康和伊立替康）是拓扑异构酶 I 的抑制剂。这些药物在临床上对多种癌症具有活性。为了了解抗癌药物 CPT 家族化疗耐药的起源，我们通过基因表达谱检查了人肝癌 HepG2 细胞中拓扑替康的药理反应，发现拓扑替康对磷脂转移蛋白 (PLTP) 基因表达具有显着诱导作用。我们发现PLTP基因表达的激活对CPT及其类似物（包括抑制拓扑异构酶I的特定对映体）具有特异性。PLTP介导的脂质向高密度脂蛋白（HDL）的转移被认为对于脂蛋白之间脂质的穿梭和重新分配很重要，脂蛋白通常通过反向胆固醇转运途径返回肝脏进行代谢。因此，我们询问升高的 PLTP 水平是否会增加药物向 HDL 的转移。我们观察到 CPT 没有在 HDL 和其他脂蛋白中积累。此外，拓扑替康治疗小鼠导致血清高密度脂蛋白显着降低，同时甘油三酯和胆固醇水平升高。这些结果表明，PLTP 不介导拓扑异构酶 I 抑制剂向血清脂蛋白的转移。然而，癌症患者接受拓扑异构酶 I 抑制剂治疗后血清 PLTP 水平升高，可作为监测高甘油三酯血症和急性胰腺炎发展的生物标志物。
Camptothecin (CPT) and its structural analogues including topotecan and irinotecan, are inhibitors of topoisomerase I. These drugs are clinically active against a broad spectrum of cancers. To understand the genesis of chemotherapeutic resistance to the CPT family of anticancer drugs, we examined by gene expression profiling the pharmacological response to topotecan in the human hepatoma HepG2 cells and found a striking induction of the phospholipid transfer protein (PLTP) gene expression by topotecan. We showed that activation of PLTP gene expression is specific to CPT and its analogues including specific enantiomers that inhibit topoisomerase I. PLTP-mediated lipid transfer to high-density lipoprotein (HDL) is thought to be important for shuttling and redistribution of lipids between lipoproteins, which are normally returned to the liver for metabolism via the reverse cholesterol transport pathway. Hence, we asked whether elevated PLTP levels might increase the transfer of drugs into HDL. We observed that CPT was not accumulated in HDL and other lipoproteins. In addition, topotecan treatment in mice caused a marked reduction in serum HDL that was accompanied by an increase in triglyceride and cholesterol levels. These results showed that PLTP does not mediate the transfer of topoisomerase I inhibitors to serum lipoproteins. However, elevated serum PLTP levels following treatment with topoisomerase I inhibitors in cancer patients may serve as a biomarker for monitoring the development of hypertriglyceridemia and acute pancreatitis.