title: Suppression of c-Myc is involved in multi-walled carbon nanotubes' down-regulation of ATP-binding cassette transporters in human colon adenocarcinoma cells.
abstract: Over-expression of ATP-binding cassette (ABC) transporters, a large family of integral membrane proteins that decrease cellular drug uptake and accumulation by active extrusion, is one of the major causes of cancer multi-drug resistance (MDR) that frequently leads to failure of chemotherapy. Carbon nanotubes (CNTs)-based drug delivery devices hold great promise in enhancing the efficacy of cancer chemotherapy. However, CNTs' effects on the ABC transporters remain under-investigated. In this study, we found that multiwalled carbon nanotubes (MWCNTs) reduced transport activity and expression of ABC transporters including ABCB1/Pgp and ABCC4/MRP4 in human colon adenocarcinoma Caco-2 cells. Proto-oncogene c-Myc, which directly regulates ABC gene expression, was concurrently decreased in MWCNT-treated cells and forced over-expression of c-Myc reversed MWCNTs' inhibitory effects on ABCB1 and ABCC4 expression. MWCNT-cell membrane interaction and cell membrane oxidative damage were observed. However, antioxidants such as vitamin C, β-mecaptoethanol and dimethylthiourea failed to antagonize MWCNTs' down-regulation of ABC transporters. These data suggest that MWCNTs may act on c-Myc, but not through oxidative stress, to down-regulate ABC transporter expression. Our findings thus shed light on CNTs' novel cellular effects that may be utilized to develop CNTs-based drug delivery devices to overcome ABC transporter-mediated cancer chemoresistance.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China.
authors.forename: Zhaojing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Ophthalmological Research, Department of Ophthalmology, Renmin Hospital of Wuhan University, 430060 Wuhan, PR China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: School of Materials and Metallurgy, Northeastern University, Shenyang 110819, PR China.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Biomedical, Dental Materials and Engineering, Graduate School of Dental Medicine, Hokkaido University, Sapporo 060-8586, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Watari
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China. Electronic address: hudanliu@hust.edu.cn.
authors.forename: Hudan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China. Electronic address: mornsmile@yahoo.com.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D037742:Nanotubes, Carbon; D018384:Oxidative Stress / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D004337:Drug Carriers; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D037742:Nanotubes, Carbon; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; C513055:ABCB1 protein, human; C073492:ABCC4 protein, human; C000715470:MAS1 protein, human; C489427:MYC protein, human
keywords: ABC transporters; Human colon adenocarcinoma; Multi-drug resistance; Multi-walled carbon nanotubes; Reactive oxygen species; c-Myc