title: Modulation of the function of the multidrug resistance-linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin.
abstract: Curcumin (curcumin I), demethoxycurcumin (curcumin II), and bisdemethoxycurcumin (curcumin III) are the major forms of curcuminoids found in the turmeric powder, which exhibit anticancer, antioxidant, and anti-inflammatory activities. In this study, we evaluated the ability of purified curcuminoids to modulate the function of either the wild-type 482R or the mutant 482T ABCG2 transporter stably expressed in HEK293 cells and drug-selected MCF-7 FLV1000 and MCF-7 AdVp3000 cells. Curcuminoids inhibited the transport of mitoxantrone and pheophorbide a from ABCG2-expressing cells. However, both cytotoxicity and [(3)H]curcumin I accumulation assays showed that curcuminoids are not transported by ABCG2. Nontoxic concentration of curcumin I, II, and III sensitized the ABCG2-expressing cells to mitoxantrone, topotecan, SN-38, and doxorubicin. This reversal was not due to reduced expression because ABCG2 protein levels were unaltered by treatment with 10 mumol/L curcuminoids for 72 hours. Curcumin I, II, and III stimulated (2.4- to 3.3-fold) ABCG2-mediated ATP hydrolysis and the IC(50)s were in the range of 7.5 to 18 nmol/L, suggesting a high affinity of curcuminoids for ABCG2. Curcuminoids also inhibited the photolabeling of ABCG2 with [(125)I]iodoarylazidoprazosin and [(3)H]azidopine as well as the transport of these two substrates in ABCG2-expressing cells. Curcuminoids did not inhibit the binding of [alpha-(32)P]8-azidoATP to ABCG2, suggesting that they do not interact with the ATP-binding site of the transporter. Collectively, these data show that, among curcuminoids, curcumin I is the most potent modulator of ABCG2 and thus should be considered as a treatment to increase the efficacy of conventional chemotherapeutic drugs.
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute/NIH, Department of Health and Human Services, Bethesda, MD 20892, USA.
authors.forename: Wanida
authors.initials: W
authors.lastname: Chearwae
authors.forename: Suneet
authors.initials: S
authors.lastname: Shukla
authors.forename: Pornngarm
authors.initials: P
authors.lastname: Limtrakul
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001386:Azides / Q000378:metabolism; D001692:Biological Transport; D002734:Chlorophyll / Q000031:analogs & derivatives / Q000378:metabolism; D003474:Curcumin / Q000378:metabolism / Q000494:pharmacology*; D004095:Dihydropyridines / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006868:Hydrolysis; D008942:Mitoxantrone / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011224:Prazosin / Q000031:analogs & derivatives / Q000378:metabolism; D018675:Toxicity Tests; D014407:Tumor Cells, Cultured
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D016588:Anticarcinogenic Agents; D001386:Azides; D004095:Dihydropyridines; D009363:Neoplasm Proteins; D002734:Chlorophyll; C017040:8-azidoadenosine 5'-triphosphate; C041130:azidopine; D000255:Adenosine Triphosphate; C041552:azidoprazosin; D008942:Mitoxantrone; C032623:pheophorbide a; D003474:Curcumin; D011224:Prazosin