RT Journal Article
SR Electronic
T1 Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance-Linked ABC transporter ABCG2
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.117.076000
DO 10.1124/dmd.117.076000
A1 Megumi Murakami
A1 Shinobu Ohnuma
A1 Michihiro Fukuda
A1 Eduardo E Chufan
A1 Katsuyoshi Kudoh
A1 Keigo Kanehara
A1 Norihiko Sugisawa
A1 Masaharu Ishida
A1 Takeshi Naitoh
A1 Hiroyuki Shibata
A1 Yoshiharu Iwabuchi
A1 Suresh V Ambudkar
A1 Michiaki Unno
YR 2017
UL http://dmd.aspetjournals.org/content/early/2017/09/13/dmd.117.076000.abstract
AB Multidrug resistance (MDR) caused by the overexpression of ATP-binding cassette (ABC) transporters in cancer cells is a major obstacle in cancer chemotherapy. Previous studies have shown that curcumin, a natural product and a dietary constituent of turmeric, inhibits the function of MDR-related ABC transporters, including ABCB1, ABCC1, and especially ABCG2. However, the limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinical setting. In this study, we investigated the effects of twenty-four synthetic curcumin analogs with increased bioavailability on the transport function of ABCG2. The screening of the 24 synthetic analogs by means of flow cytometry revealed that four of the curcumin analogs, namely, GO-Y030, GO-Y078, GO-Y168, and GO-Y172, significantly inhibited the efflux of the ABCG2 substrates, mitoxantrone and pheophorbide A, from ABCG2-overexpressing K562/BCRP cells. Biochemical analyses showed that GO-Y030, GO-Y078, and GO-Y172 stimulated the ATPase activity of ABCG2 at nanomolar concentrations and inhibited the photolabeling of ABCG2 with iodoarylazidoprazosin, suggesting that these analogs interact with the substrate-binding sites of ABCG2. In addition, when used in cytotoxicity assays, GO-Y030 and GO-Y078 were found to improve the sensitivity of the anti-cancer drug, SN-38, in K562/BCRP cells. Taken together, these results suggest that non-toxic synthetic curcumin analogs with increased bioavailability, especially GO-Y-030 and GO-Y078, inhibit the function of ABCG2 by directly interacting at the substrate-binding site. These synthetic curcumin analogs could therefore be developed as potent modulators to overcome ABCG2-mediated MDR in cancer cells.