Altered phospholipid transfer protein gene expression and serum lipid profile by topotecan.
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.
Saunders
Rudel A
RA
Department of Medicine, The University of Toledo, College of Medicine, Toledo, OH, United States.
Fujii
Kazuyuki
K
Alabanza
Leah
L
Ravatn
Roald
R
Kita
Tsunekazu
T
Kudoh
Kazuya
K
Oka
Masahiro
M
Chin
Khew-Voon
KV
D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D049294:Phospholipid Transfer Proteins / Q000096:biosynthesis* / Q000235:genetics*; D019772:Topotecan / Q000494:pharmacology*
D008055:Lipids; D049294:Phospholipid Transfer Proteins; D019772:Topotecan