Altered phospholipid transfer protein gene expression and serum lipid profile by topotecan

Department of Medicine, The University of Toledo, College of Medicine, Toledo, OH, United States.
Biochemical pharmacology (Impact Factor: 5.01). 04/2010; 80(3):362-9. DOI: 10.1016/j.bcp.2010.04.015
Source: PubMed


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.

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Available from: Rudel Saunders, Apr 09, 2014
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    • "C at 10 mM, 5-FU at 300 ng/ml, camptothecin at 0.5 mM, SN-38 at 10 ng/ml, topotecan at 0.1 mg/ml, and etoposide at 50 mM) are clinically relevant and/or approximate those that have been frequently used in similar cell culture studies (Italia et al., 1983; Piret et al., 2006; Roudier et al., 2006; Liedtke et al., 2007; L'Espérance et al., 2008; Malmlof et al., 2008; Cosse et al., 2010; Saunders et al., 2010; Basseville et al., 2011; Hu et al., 2014c). Total RNA was extracted using the RNeasy Mini Kit (QIAGEN, Valencia, CA) and converted to cDNA using Invitrogen reverse transcription reagents (Mulgrave, VIC, Australia) as previously reported (Hu and Mackenzie, 2009). "
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