title: Heterocyclic cyclohexanone monocarbonyl analogs of curcumin can inhibit the activity of ATP-binding cassette transporters in cancer multidrug resistance.
abstract: Curcumin (CUR) is a phytochemical that inhibits the xenobiotic ABC efflux transporters implicated in cancer multidrug resistance (MDR), such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins 1 and 5 (MRP1 and MRP5). The use of CUR in the clinic however, is complicated by its instability and poor pharmacokinetic profile. Monocarbonyl analogs of CUR (MACs) are compounds without CUR's unstable β-diketone moiety and were reported to have improved stability and in vivo disposition. Whether the MACs can be used as MDR reversal agents is less clear, as the absence of a β-diketone may negatively impact transporter inhibition. In this study, we investigated 23 heterocyclic cyclohexanone MACs for inhibitory effects against P-gp, BCRP, MRP1 and MRP5. Using flow cytometry and resistance reversal assays, we found that many of these compounds inhibited the transport activity of the ABC transporters investigated, often with much greater potency than CUR. Overall the analogs were most effective at inhibiting BCRP and we identified three compounds, A12 (2,6-bis((E)-2,5-dimethoxy-benzylidene)cyclohexanone), A13 (2,6-bis((E)-4-hydroxyl-3-methoxybenzylidene)-cyclohexanone) and B11 (3,5-bis((E)-2-fluoro-4,5-dimethoxybenzylidene)-1-methylpiperidin-4-one), as the most promising BCRP inhibitors. These compounds inhibited BCRP activity in a non-cell line, non-substrate-specific manner. Their inhibition occurred by direct transporter interaction rather than modulating protein or cell surface expression. From these results, we concluded that MACs, such as the heterocyclic cyclohexanone analogs in this study, also have potential as MDR reversal agents and may be superior alternatives to the unstable parent compound, CUR.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Electronic address: j.revalde@auckland.ac.nz.
authors.forename: Jezrael L
authors.initials: JL
authors.lastname: Revalde
authors.affiliation: School of Interprofessional Health Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand. Electronic address: yan.li@aut.ac.nz.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Chemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Bill C
authors.initials: BC
authors.lastname: Hawkins
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Rhonda J
authors.initials: RJ
authors.lastname: Rosengren
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: James W
authors.initials: JW
authors.lastname: Paxton
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D057809:HEK293 Cells; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007313:Insecta; D061985:Madin Darby Canine Kidney Cells
chemical_list: D018528:ATP-Binding Cassette Transporters; D003512:Cyclohexanones; D006571:Heterocyclic Compounds; C036468:cyclohexanone; D003474:Curcumin
keywords: A12 (PubChem CID: 1811454); A13 (PubChem CID: 1550234); ABC transporters; B11 (PubChem CID: 49866299); BCRP; C10 (PubChem CID: 46505934); Cancer multidrug resistance; Curcumin; Curcumin (PubChem CID: 969516); Curcumin analogs