title: DNA topoisomerase II inhibitors induce macrophage ABCA1 expression and cholesterol efflux-an LXR-dependent mechanism.
abstract: ATP-binding cassette transporter A1 (ABCA1) facilitates cholesterol efflux and thereby inhibits lipid-laden macrophage/foam cell formation and atherosclerosis. ABCA1 expression is transcriptionally regulated by activation of liver X receptor (LXR). Both etoposide and teniposide are DNA topoisomerase II (Topo II) inhibitors and are chemotherapeutic medications used in the treatment of various cancers. Interestingly, etoposide inhibits atherosclerosis in rabbits by unclear mechanisms. Herein, we report the effects of etoposide and teniposide on macrophage ABCA1 expression and cholesterol efflux. Both etoposide and teniposide increased macrophage free cholesterol efflux. This increase was associated with increased ABCA1 mRNA and protein expression. Etoposide and teniposide also increased ABCA1 promoter activity in an LXR-dependent manner and formation of the LXRE-LXR/RXR complex indicating that transcriptional induction had occurred. Expression of ABCG1 and fatty acid synthase (FAS), another two LXR-targeted genes, was also induced by etoposide and teniposide. In vivo, administration of mice with either etoposide or teniposide induced macrophage ABCA1 expression and enhanced reverse cholesterol transport from macrophages to feces. Taken together, our study indicates that etoposide and teniposide increase macrophage ABCA1 expression and cholesterol efflux that may be attributed to the anti-atherogenic properties of etoposide. Our study also describes a new function for Topo II inhibitors in addition to their role in anti-tumorigenesis.
authors: Nankai University, Tianjin, China.
authors: Ling
authors: L
authors: Zhang
authors: Meixiu
authors: M
authors: Jiang
authors: Yongsheng
authors: Y
authors: Shui
authors: Yuanli
authors: Y
authors: Chen
authors: Qixue
authors: Q
authors: Wang
authors: Wenquan
authors: W
authors: Hu
authors: Xingzhe
authors: X
authors: Ma
authors: Xiaoju
authors: X
authors: Li
authors: Xin
authors: X
authors: Liu
authors: Xingyue
authors: X
authors: Cao
authors: Mengyang
authors: M
authors: Liu
authors: Yajun
authors: Y
authors: Duan
authors: Jihong
authors: J
authors: Han
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005047:Etoposide / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D013713:Teniposide / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D047488:Retinoid X Receptors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D013713:Teniposide; D002784:Cholesterol