title: Obatoclax as a perpetrator in drug-drug interactions and its efficacy in multidrug resistance cell lines.
abstract: OBJECTIVE
  Obatoclax is a pan-Bcl-2 inhibitor with promising efficacy, especially when combined with other antineoplastic agents. Pharmacokinetic drug-drug interactions can occur systemically and at the level of the tumour cell. Thus, this study scrutinised the interaction potential of obatoclax in vitro.
  
  
  METHODS
  Obatoclax was screened for P-gp inhibition by calcein assay, for breast cancer resistance protein (BCRP) inhibition by pheophorbide A assay and for inhibition of cytochrome P450 isoenzymes (CYPs) by commercial kits. Induction of mRNA of drug-metabolising enzymes and drug transporters was quantified in LS180 cells via real-time polymerase chain reaction and involvement of nuclear receptors was assessed by reporter gene assays. Proliferation assays were used to assess whether obatoclax retains its efficacy in cell lines overexpressing BCRP, P-glycoprotein (P-gp) or multidrug resistance-associated protein 2 (MRP2).
  
  
  RESULTS
  Obatoclax induced the mRNA expression of several genes (e.g. CYP1A1, CYP1A2 and ABCG2 (five to seven-fold) through activation of the aryl hydrocarbon receptor in the nanomolar range. Obatoclax inhibits P-gp, BCRP and some CYPs at concentrations exceeding plasma levels. P-gp, MPR2 or BCRP overexpression did not influence the efficacy of obatoclax.
  
  
  CONCLUSIONS
  Obatoclax retains its efficacy in cells overexpressing P-gp, MRP2 or BCRP and might act as a perpetrator drug in interactions with drugs, for example being substrates of CYP1A2 or BCRP.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Theile
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Allendorf
authors.affiliation: National Centre for Tumour Diseases, Department of Medical Oncology, Internal Medicine VI, University of Heidelberg, Heidelberg, Germany.
authors.forename: Bruno Christian
authors.initials: BC
authors.lastname: Köhler
authors.affiliation: National Centre for Tumour Diseases, Department of Medical Oncology, Internal Medicine VI, University of Heidelberg, Heidelberg, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Jassowicz
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007211:Indoles; D018374:LLC-PK1 Cells; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D003577:Cytochrome P-450 Enzyme System; D007211:Indoles; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011758:Pyrroles; D012333:RNA, Messenger; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C520962:obatoclax
keywords: CYPs; drug transporters; drug-drug interaction; obatoclax