title: Demethoxycurcumin modulates human P-glycoprotein function via uncompetitive inhibition of ATPase hydrolysis activity.
abstract: Curcuminoids are major components of Curcuma longa L., which is widely used as spice in food. This study aimed at identifying whether curcumin, demethoxycurcumin, and bisdemethoxycurcumin could modulate efflux function of human P-glycoprotein and be used as chemosensitizers in cancer treatments. Without altering P-glycoprotein expression levels and conformation, the purified curcuminoids significantly inhibited P-glycoprotein efflux function. In rhodamine 123 efflux and calcein-AM accumulation assays, demethoxycurcumin demonstrated the highest inhibition potency (inhibitory IC50 = 1.56 ± 0.13 μM) among the purified curcuminoids, as well as in the fold of reversal assays. Demethoxycurcumin inhibited P-glycoprotein-mediated ATP hydrolysis under concentrations of <1 μM and efficiently inhibited 200 μM verapamil-stimulated ATPase activity, indicating a high affinity of demethoxycurcumin for P-glycoprotein. These results suggested that demethoxycurcumin may be a potential additive natural product in combination with chemotherapeutic agents in drug-resistant cancers.
authors.affiliation: Department of Pharmacy, College of Pharmacy, China Medical University , Taichung, Taiwan.
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Teng
authors.forename: Yow-Wen
authors.initials: YW
authors.lastname: Hsieh
authors.forename: Chin-Chuan
authors.initials: CC
authors.lastname: Hung
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Lin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D036381:Diarylheptanoids; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D005456:Fluorescent Dyes; D006801:Humans; D006868:Hydrolysis; D020112:Rhodamine 123
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D036381:Diarylheptanoids; D005456:Fluorescent Dyes; D020112:Rhodamine 123; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D003474:Curcumin; C050229:demethoxycurcumin
keywords: P-glycoprotein; curcuminoids; demethoxycurcumin; kinetic mechanism; multidrug resistance