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CS, in that the resistant cells are actually less sensitive against each compound individually, whereas the combination of cur- cumin with either gA or ouabain evokes CS. Table 1 shows that in the presence of curcumin, resistant cells died at four times lower gA and two times lower ouabain concentrations than parental cells. Based on these results, we tested whether curcumin, gA, or ouabain would have a similar sensitization effect in ABCG2-expressing cells when adminis- tered at subtoxic concentrations together with mitoxantrone, a well known substrate of ABCG2 transporters (5). Table 1 shows that in the presence of curcumin, HEK-ABCG2 cells were still more resistant toward mitoxantrone than parental cells. Although curcumin reduced (i.e. reversed) the resistance of these cells toward mitoxantrone significantly, it could not cause CS as we observed in Fig. 1 with the combination of curcumin with either gA or ouabain. The presence of subtoxic concentra- tions of gA or ouabain had only a small effect on the resistance of ABCG2 cells toward mitoxantrone. Therefore, the specific toxicity of a combination of the ABCG2 modulator curcumin with gA or ouabain toward HEK-ABCG2 cells could not be replicated with a combination of the well known ABCG2 trans- porter substrate mitoxantrone. Inhibiting the Function of ABCG2 Transporters Reverses Cytotoxicity of Curcumin in Combination with gA or Ouabain toward HEK-ABCG2 Cells—To determine whether the selec- tive cell death of HEK-ABCG2 cells by treatment with curcu- min and gA or curcumin with ouabain was dependent on the activity of the ABCG2 transporter, we incubated cells with sub- toxic doses of curcumin in combination with gA in the presence or absence of 10 M FTC, a specific inhibitor of ATP hydrolysis and thus of active transport by the ABCG2 transporter (37). We found that in the presence of FTC, the selective cytotoxicity of curcumin and gA or curcumin and ouabain toward HEK- ABCG2 cells was lost, and the viability was restored to that of parental cells (Fig. 2). This result indicates that active ABCG2 transporters were indeed responsible for selective killing of HEK-ABCG2 cells in the presence of curcumin with either gA or ouabain. A Combination of Curcumin with Either gA or Ouabain Inhibits Efflux by ABCG2—To determine whether subtoxic concentrations of curcumin in combination with either gA or ouabain would affect the efflux activity of ABCG2 transporters, FIGURE 3. Effect of 2 M curcumin in combination with 35 nM gA or with 7.5 nM ouabain on the accumulation of Bp in HEK-293 control and HEK- ABCG2 cells. HEK-293 control cells (A and B) and HEK-ABCG2 cells (C and D) were incubated in the absence (red curve) or presence of 250 nM Bp alone (peak 1) or in combination with 10 M FTC (peak 2), 35 nM gA (peak 3), 2 M curcumin (peak 4), a combination of 35 nM gA and 2 M curcumin (peak 5), 7.5 nM ouabain (peak 6), and a combination of 7.5 nM ouabain and 2 M curcumin (peak 7). we used flow cytometry to quantify the efflux of the fluorescent substrate BODIPY-prazosin (Bp) in HEK-ABCG2 and parental cells in the presence and absence of curcumin in combination with gA or ouabain (Fig. 3) (8). Table 2 summarizes the MFI and the percentage of efflux in HEK-ABCG2 cells under various conditions. Curcumin, gA, or ouabain individually had either no effect or a small effect on efflux of BODIPY-prazosin by ABCG2. In contrast, the combination of curcumin with gA inhibited efflux by ABCG2 completely and was as effective as Drug Combinations Evoke Collateral Sensitivity against ABCG2 FIGURE 2. Reversal of selective cytotoxicity by curcumin in combination with either gA or ouabain in HEK-ABCG2 cells in the presence of FTC. Cell viability of HEK-293 control cells (black) and HEK-ABCG2 cells (red) exposed to increasing doses of gA (A) or ouabain (B) in the presence of 2 M curcumin and in the absence (dashed curves) or presence (solid curves) of 10 M FTC. NOVEMBER 7, 2014 • VOLUME 289 • NUMBER 45 JOURNAL OF BIOLOGICAL CHEMISTRY 31401PDF Image | Curcumin with Either Gramicidin or Ouabain
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