Abstract 3242: Synthetic analogs of curcumin as modulators of multidrug resistance-linked ABC transporters

Abstract

Abstract Cancer patients often develop resistance to anticancer drugs. ATP-binding cassette (ABC) transporter-mediated drug efflux is one of the mechanisms responsible for development of resistance to anticancer drugs. The present study investigates the use of curcumin, a natural product and a dietary constituent of turmeric, which inhibits the function of three ABC drug transporters including ABCB1, ABCC1 and ABCG2. However, limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinic. We focused on curcumin analogs that were synthesized at Tohoku University and have been shown to exhibit higher bioavailability than natural curcumin to test whether the synthetic analogs also inhibit the function of ABC drug transporters. To investigate this, KB-V1 and K562/BCRP cell lines overexpressing ABCB1 and ABCG2 were used for the experiments. For these studies, we screened nineteen synthetic analogs of curcumin for their effect on the transport function of ABCB1 and ABCG2 by flow cytometry. Four curcumin analogs, GO-Y030, GO-Y078, GO-Y168 and GO-Y172 inhibited efflux of mitoxantrone mediated by ABCG2 and sensitized ABCG2-expressing K562 leukemic cells to the anticancer drug, SN-38 in cell toxicity assays. Some of the curcumin analogs (GO-Y030, GO-Y078, GO-Y172) stimulated ATPase activity of ABCG2 at nanomolar concentrations (EC50 = 480 ± 0.06, 790 ± 0.10, 930 ± 0.12 nM). In addition, GO-Y030, GO-Y078, GO-Y168, GO-Y172 analogs also inhibited photolabeling of ABCG2 in MCF-7-FL plasma membranes with iodoarylazidoprazosin, which is transported by this transporter. These data demonstrate that similar to curcumin, synthetic curcumin analogs also interact at the drug-binding pocket of ABCG2. In aggregate, these results suggest that non-toxic synthetic curcumin analogs with increased bioavailability may be useful to reverse ABCG2-mediated resistance to anticancer agents. Citation Format: Megumi Obara, Shinobu Ohnuma, Eduardo E. Chufan, Masaharu Ishida, Katsuyoshi Kudoh, Norihiko Sugisawa, Hideo Ohtsuka, Takeshi Naitoh, Hiroyuki Shibata, Yoshiharu Iwabuchi, Suresh V. Ambudkar, Michiaki Unno. Synthetic analogs of curcumin as modulators of multidrug resistance-linked ABC transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3242. doi:10.1158/1538-7445.AM2017-3242