PMID- 25543853 OWN - NLM STAT- MEDLINE DCOM- 20150421 LR - 20171213 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 93 IP - 3 DP - 2015 Feb 1 TI - Heterocyclic cyclohexanone monocarbonyl analogs of curcumin can inhibit the activity of ATP-binding cassette transporters in cancer multidrug resistance. PG - 305-17 LID - S0006-2952(14)00726-6 [pii] LID - 10.1016/j.bcp.2014.12.012 [doi] AB - 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 beta-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 beta-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. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Revalde, Jezrael L AU - Revalde JL AD - 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. FAU - Li, Yan AU - Li Y AD - 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. FAU - Hawkins, Bill C AU - Hawkins BC AD - Department of Chemistry, University of Otago, Dunedin, New Zealand. FAU - Rosengren, Rhonda J AU - Rosengren RJ AD - Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand. FAU - Paxton, James W AU - Paxton JW AD - Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141225 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (ATP-Binding Cassette Transporters) RN - 0 (Cyclohexanones) RN - 0 (Heterocyclic Compounds) RN - 5QOR3YM052 (cyclohexanone) RN - IT942ZTH98 (Curcumin) SB - IM MH - ATP-Binding Cassette Transporters/*antagonists & inhibitors/metabolism MH - Animals MH - Cell Line, Tumor MH - Curcumin/*analogs & derivatives/*pharmacology MH - Cyclohexanones/chemistry/*pharmacology MH - Dogs MH - Dose-Response Relationship, Drug MH - Drug Resistance, Multiple/*drug effects/physiology MH - Drug Resistance, Neoplasm/*drug effects/physiology MH - HEK293 Cells MH - Heterocyclic Compounds/chemistry/pharmacology MH - Humans MH - Insecta MH - Madin Darby Canine Kidney Cells OTO - NOTNLM OT - A12 (PubChem CID: 1811454) OT - A13 (PubChem CID: 1550234) OT - ABC transporters OT - B11 (PubChem CID: 49866299) OT - BCRP OT - C10 (PubChem CID: 46505934) OT - Cancer multidrug resistance OT - Curcumin OT - Curcumin (PubChem CID: 969516) OT - Curcumin analogs EDAT- 2014/12/30 06:00 MHDA- 2015/04/22 06:00 CRDT- 2014/12/30 06:00 PHST- 2014/11/13 00:00 [received] PHST- 2014/12/16 00:00 [revised] PHST- 2014/12/16 00:00 [accepted] PHST- 2014/12/30 06:00 [entrez] PHST- 2014/12/30 06:00 [pubmed] PHST- 2015/04/22 06:00 [medline] AID - S0006-2952(14)00726-6 [pii] AID - 10.1016/j.bcp.2014.12.012 [doi] PST - ppublish SO - Biochem Pharmacol. 2015 Feb 1;93(3):305-17. doi: 10.1016/j.bcp.2014.12.012. Epub 2014 Dec 25.