Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from Turmeric powder.
P-glycoprotein (Pgp, ABCB1) is an ATP-dependent drug efflux pump linked to development of multidrug resistance (MDR) in cancer cells. Previously [Biochem Pharmacol 2002;64:573-82], we reported that a curcumin mixture could modulate both function and expression of Pgp. This study focuses on the effect of three major curcuminoids--curcumin I, II and III purified from a curcumin mixture--on modulation of Pgp function in a multidrug resistant human cervical carcinoma cell line (KB-V1). The similar IC(50) values for cytotoxicity of curcuminoids of KB-V1, and KB-3-1 (parental drug sensitive cell line) suggest that these curcuminoids may not be substrates for Pgp. Treating the cells with non-toxic doses of curcuminoids increased their sensitivity to vinblastine only in the Pgp expressing drug resistant cell line, KB-V1, and curcumin I retained the drug in KB-V1 cells more effectively than curcumin II and III, respectively. Effects of each curcuminoid on rhodamine123, calcein-AM, and bodipy-FL-vinblastine accumulation confirmed these findings. Curcumin I, II and III increased the accumulation of fluorescent substrates in a dose-dependent manner, and at 15 microM, curcumin I was the most effective. The inhibitory effect in a concentration-dependent manner of curcuminoids on verapamil-stimulated ATPase activity and photoaffinity labeling of Pgp with the [(125)I]-iodoarylazidoprazosin offered additional support; curcumin I was the most potent modulator. Taken together, these results indicate that curcumin I is the most effective MDR modulator among curcuminoids, and may be used in combination with conventional chemotherapeutic drugs to reverse MDR in cancer cells.
Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
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Chearwae
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Anuchapreeda
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Nandigama
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Ambudkar
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Limtrakul
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001386:Azides / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D030024:Curcuma; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D036381:Diarylheptanoids; D004338:Drug Combinations; D004347:Drug Interactions; D005452:Fluoresceins / Q000493:pharmacokinetics; D006801:Humans; D007457:Iodine Radioisotopes; D007624:KB Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D019920:Photoaffinity Labels / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry*; D011224:Prazosin / Q000031:analogs & derivatives* / Q000378:metabolism; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D000970:Antineoplastic Agents; D001386:Azides; D003474:Curcumin; D036381:Diarylheptanoids; D004338:Drug Combinations; D005452:Fluoresceins; D007457:Iodine Radioisotopes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019920:Photoaffinity Labels; D010936:Plant Extracts; D011224:Prazosin; D020112:Rhodamine 123; D014747:Vinblastine; C085925:calcein AM; C475935:curcumin III; C012596:turmeric extract; C041552:azidoprazosin; C050229:demethoxycurcumin