Modulation of the function of the multidrug resistance-linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin.
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.
Chearwae
Wanida
W
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute/NIH, Department of Health and Human Services, Bethesda, MD 20892, USA.
Shukla
Suneet
S
Limtrakul
Pornngarm
P
Ambudkar
Suresh V
SV
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
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