TY - JOUR
T1 - Synthetic analogs of curcumin modulate the function of multidrug resistance–linked ATP-binding cassette transporter ABCG2
AU - Murakami, Megumi
AU - Ohnuma, Shinobu
AU - Fukuda, Michihiro
AU - Chufan, Eduardo E.
AU - Kudoh, Katsuyoshi
AU - Kanehara, Keigo
AU - Sugisawa, Norihiko
AU - Ishida, Masaharu
AU - Naitoh, Takeshi
AU - Shibata, Hiroyuki
AU - Iwabuchi, Yoshiharu
AU - Ambudkar, Suresh V.
AU - Unno, Michiaki
N1 - Funding Information:
This work was supported by grant-in-aid for scientific research from the Japan Society for the Promotion of Science [Grant JP 25861149]. E.E.C. and S.V.A. were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. https://doi.org/10.1124/dmd.117.076000.
Publisher Copyright:
Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2017/11
Y1 - 2017/11
N2 - 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 24 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 (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/breast cancer resistance protein (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 anticancer drug, SN-38, in K562/BCRP cells. Taken together, these results suggest that nontoxic synthetic curcumin analogs with increased bioavailability, especially GO-Y030 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.
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 24 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 (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/breast cancer resistance protein (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 anticancer drug, SN-38, in K562/BCRP cells. Taken together, these results suggest that nontoxic synthetic curcumin analogs with increased bioavailability, especially GO-Y030 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.
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U2 - 10.1124/dmd.117.076000
DO - 10.1124/dmd.117.076000
M3 - Article
C2 - 28904007
AN - SCOPUS:85031405307
SN - 0090-9556
VL - 45
SP - 1166
EP - 1177
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 11
ER -
