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.
Chearwae
W
W
Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Anuchapreeda
S
S
Nandigama
K
K
Ambudkar
S V
SV
Limtrakul
P
P
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