title: The inhibitory effects of camptothecin (CPT) and its derivatives on the substrate uptakes mediated by human solute carrier transporters (SLCs).
abstract: 1. Camptothecin (CPT) and its derivatives are potent candidate compounds in treating cancers. However, their clinical applications are largely restricted by severe toxicities. 2. The solute carrier transporters (SLCs), particularly the organic anion transporting polypeptides and organic anion/cation transporters (OATs/OCTs) are widely expressed in human key organs and responsible for the cellular influx of many substances including endogenous substrates and many clinically important drugs. Drug-drug interactions through SLCs often result in unsatisfied therapeutic outcomes and/or unexpected toxicities. 3. This study investigated the inhibitory effects of CPT and its eight derivatives on the cellular uptake of specific substrates mediated by the essential SLCs in over-expressing Human embryonic kidney 293 cells. 4. Our data revealed that CPT, 10-hydroxycamptothecin (HCPT), 10-methoxycamptothecin (MCPT) and 9-nitrocamptothecin (9NC) significantly inhibit the uptake activity of OAT3. 9NC also inhibited the substrate transport mediated by OAT1. The substrate uptakes of OAT1, OCTN1 and OCTN2 were significantly decreased in the presence of CZ112, while CPT-11 potently down-regulated the transport activity of OCT1 and OCT3. 5. In summary, our study demonstrated that CPT and its eight derivatives selectively inhibit the substrate uptakes mediated by the essential SLCs. This information contributes to understanding the localized toxicity of CPTs and provides novel molecular targets for the therapeutic optimization of CPTs in the future.
authors.affiliation: a Alkali Soil Natural Environmental Science Center, Northeast Forestry University/Key Laboratory of Saline-alkali Vegetation Ecology Restoration in Oil Field, Ministry of Education , Harbin , P.R. China .|b Faculty of Pharmacy , University of Sydney , Sydney , NSW , Australia .
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.affiliation: b Faculty of Pharmacy , University of Sydney , Sydney , NSW , Australia .
authors.forename: Ting
authors.initials: T
authors.lastname: Chan
authors.affiliation: c Save Sight Institute, University of Sydney , Sydney , NSW , Australia , and.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
authors.affiliation: a Alkali Soil Natural Environmental Science Center, Northeast Forestry University/Key Laboratory of Saline-alkali Vegetation Ecology Restoration in Oil Field, Ministry of Education , Harbin , P.R. China .
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Yan
authors.affiliation: d The CHRISTUS Stehlin Foundation for Cancer Research , Houston , TX , USA.
authors.forename: Zhisong
authors.initials: Z
authors.lastname: Cao
authors.affiliation: a Alkali Soil Natural Environmental Science Center, Northeast Forestry University/Key Laboratory of Saline-alkali Vegetation Ecology Restoration in Oil Field, Ministry of Education , Harbin , P.R. China .
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: b Faculty of Pharmacy , University of Sydney , Sydney , NSW , Australia .
authors.forename: Fanfan
authors.initials: F
authors.lastname: Zhou
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology*; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D027361:Organic Anion Transporters / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D027361:Organic Anion Transporters; D002166:Camptothecin
keywords: Camptothecin; drug–drug interaction; organic anion transporters; organic anion transporting polypeptides; organic cation transporters