Modulation of the function of the multidrug resistance–linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin

Chearwae, Wanida; Shukla, Suneet; Limtrakul, Pornngarm; Ambudkar, Suresh V.

doi:10.1158/1535-7163.mct-06-0087

Cited by 110 publications

(81 citation statements)

References 44 publications

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“…We did observe that some cell lines are naturally more resistant to NSC73306. It is not unusual for a particular drug to display varying levels of toxicity in cell lines originating from different tissues (41), but in this instance, intrinsic P-glycoprotein levels in the different cell lines may be responsible for differential cytotoxicity. Low levels of MDR1 mRNA are present in HEK293 cells, which are more NSC73306 sensitive (NSC73306 IC 50 = 7.29 Amol/L), but NSC73306.…”

Section: Discussionmentioning

confidence: 99%

Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance–linked ABCG2 transporter

Shukla

Calcagno

et al. 2007

Molecular Cancer Therapeutics

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166

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Multidrug resistance due to reduced drug accumulation is a phenomenon predominantly caused by the overexpression of members of the ATP-binding cassette (ABC) transporters, including ABCB1 (P-glycoprotein), ABCG2, and several ABCC family members [multidrug resistanceassociated protein (MRP)]. We previously reported that a thiosemicarbazone derivative, NSC73306, is cytotoxic to carcinoma cells that overexpress functional P-glycoprotein, and it resensitizes these cells to chemotherapeutics. In this study, we investigated the effect of NSC73306 on cells overexpressing other ABC drug transporters, including ABCG2, MRP1, MRP4, and MRP5. Our findings showed that NSC73306 is not more toxic to cells that overexpress these transporters compared with their respective parental cells, and these transporters do not confer resistance to NSC73306 either. In spite of this, we observed that NSC73306 is a transport substrate for ABCG2 that can effectively inhibit ABCG2-mediated drug transport and reverse resistance to both mitoxantrone and topotecan in ABCG2-expressing cells. Interactions between NSC73306 and the ABCG2 drug-binding site(s) were confirmed by its stimulatory effect on ATPase activity (140 -150 nmol/L concentration required for 50% stimulation) and by inhibition of [ 125 I]iodoarylazidoprazosin photolabeling (50% inhibition at 250 -400 nmol/L) of the substrate-binding site(s). Overall, NSC73306 seems to be a potent modulator of ABCG2 that does not interact with MRP1, MRP4, or MRP5. Collectively, these data suggest that NSC73306 can potentially be used, due to its dual mode of action, as an effective agent to overcome drug resistance by eliminating P-glycoprotein -overexpressing cells and by acting as a potent modulator that resensitizes ABCG2-expressing cancer cells to chemotherapeutics.

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Section: Discussionmentioning

confidence: 99%

Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance–linked ABCG2 transporter

Shukla

Calcagno

et al. 2007

Molecular Cancer Therapeutics

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166

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“…Curcuminoids, from the rhizomes of Curcuma longa, have been reported to reverse the drug resistance phenotype in cancer cells overexpressing ABC transporters, viz., ABCB1, ABCG2, and ABCC1 (2,4,5). Curcuminoids blocked the efflux of fluorescent substrates calcein AM, rhodamine 123, and bodipy-FL-vinblastine in MDR cervical carcinoma cell lines overexpressing ABCB1 and the efflux of mitoxantrone and pheophorbide A, mediated by ABCG2, in HEK293 cells (3,4).…”

mentioning

confidence: 99%

Curcumin Modulates Efflux Mediated by Yeast ABC Multidrug Transporters and Is Synergistic with Antifungals

Sharma¹,

Manoharlal²,

Shukla

et al. 2009

Antimicrob Agents Chemother

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Curcumin (CUR), a natural product of turmeric, from rhizomes of Curcuma longa, is a known agent of reversal of drug resistance phenotypes in cancer cells overexpressing ATP-binding cassette (ABC) transporters, viz., ABCB1, ABCG2, and ABCC1. In the present study, we evaluated whether CUR could also modulate multidrug transporters of yeasts that belong either to the ABC family or to the major facilitator superfamily (MFS). The effect of CUR on multidrug transporter proteins was demonstrated by examining rhodamine 6G (R6G) efflux in Saccharomyces cerevisiae cells overexpressing the Candida albicans ABC transporters Cdr1p and Cdr2p (CaCdr1p and CaCdr2p, respectively) and the MFS transporters CaMdr1p and S. cerevisiae Pdr5p. CUR decreased the extracellular concentration of R6G in ABC transporter-expressing cells but had no effect on methotrexate efflux mediated through the MFS transporter CaMdr1p. CUR competitively inhibited R6G efflux and the photolabeling of CaCdr1p by [ 125 I]iodoarylazidoprazosin, a drug analogue of the substrate prazosin (50% inhibitory concentration, 14.2 M). Notably, the mutant variants of CaCdr1p that displayed abrogated efflux of R6G also showed reduced modulation by CUR. Drug susceptibility testing of ABC proteinexpressing cells by spot assays and checkerboard tests revealed that CUR was selectively synergistic with drug substrates such as R6G, ketoconazole, itraconazole, and miconazole but not with fluconazole, voriconazole, anisomycin, cycloheximide, or FK520. Taken together, our results provide the first evidence that CUR modulates only ABC multidrug transporters and could be exploited in combination with certain conventional antifungal drugs to reverse multidrug resistance in Candida cells.

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“…GO-Y139 1.6 6 2.6 GO-Y022 51.8 GO-Y030 84.3 6 3.5 GO-Y144 0.0 6 2.4 GO-Y135 26.6 6 2.7 GO-Y078 82.9 6 3.4 GO-Y146 15.2 6 1.2 GO-Y150 28.2 6 6.0 GO-Y168 83.2 6 6.8 GO-Y148 8.6 GO-Y152 69.8 6 3.4 GO-Y172 77.4 6 1.2 GO-Y149 9.2 GO-Y153 30.5 6 9.9 Curcumin 99.5 6 8.23 GO-Y151 6.1 GO-Y156 56.4 6 6.1 GO-Y157 0.3 GO-Y160 29.9 6 1.3 GO-Y171 14.9 6 1.9 GO-Y161 44.4 6 3.2 GO-Y162 51.5 6 9.0 GO-Y163 58.7 6 2.2 GO-Y167 52.0 6 15.9 GO-Y174 37.1 6 2.2 ]IAAP (2200 Ci/mmol) was added, and the mixture was irradiated with a 365 nm of UV light in ice-cold water for 10 minutes. An immunoprecipitation protocol was performed to ensure the reaction was specific for ABCG2 by adding BXP-21 antibody (Chearwae et al, 2006a). The samples were processed, and the photoaffinity labeling of […”

Section: Synthetic Curcumin Analogs Modulate the Function Of Abcg2mentioning

confidence: 99%

“…It is a well studied phytochemical that has the potential to suppress the growth of many cancer cell lines (Sa and Das, 2008;Lu et al, 2013). It has been shown that curcumin and its metabolites or constituents reverse the drug resistance in cells expressed by ABCB1, ABCC1, and especially ABCG2 (Anuchapreeda et al, 2002;Chearwae et al, 2004Chearwae et al, , 2006a. However, the characteristics of curcumin, which include hydrophobicity, low absorption, and rapid metabolism, caused limitations in clinical application (Sharma et al, 2004;Garcea et al, 2005;Goel et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance–Linked ATP-Binding Cassette Transporter ABCG2

et al. 2017

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Multidrug resistance (MDR) caused by the overexpression of ATPbinding 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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Modulation of the function of the multidrug resistance–linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin

Cited by 110 publications

References 44 publications

Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance–linked ABCG2 transporter

Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance–linked ABCG2 transporter

Curcumin Modulates Efflux Mediated by Yeast ABC Multidrug Transporters and Is Synergistic with Antifungals

Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance–Linked ATP-Binding Cassette Transporter ABCG2

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