Curcumin with Either Gramicidin or Ouabain

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Curcumin with Either Gramicidin or Ouabain ( curcumin-with-either-gramicidin-or-ouabain )

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Drug Combinations Evoke Collateral Sensitivity against ABCG2 FIGURE 1. A combination of curcumin with either gA or ouabain selectively kills cells with ABCG2-induced MDR phenotype. A, sensitivity of parental (HEK-293 control) cells (black) and HEK-ABCG2 cells (red) to gA in the absence (solid curves) or presence (dashed curves) of 2 􏰙M curcumin. B, sensitivity of HEK-293 control (black) and HEK-ABCG2 cells (red) to ouabain in the absence (solid curves) or presence (dashed curves) of 2 􏰙M curcumin. C and D, fluorescence- based life versus death assay of HEK-293 control (top panels) and HEK-ABCG2 cells (bottom panels) after 72 h of incubation with the specified compound(s). TABLE 1 IC50 values, relative resistance, and reversal of resistance of HEK-293 parental cells and HEK-ABCG2 cells towards curcumin, gA, ouabain, and mitoxantrone Compound Curcumin aloned Curcumin 􏰚 10 􏰙M FTC Gramicidin alone Gramicidin 􏰚 2 􏰙M curcumin Gramicidin 􏰚 2 􏰙M curcumin 􏰚 10 􏰙M FTC Ouabain alone Ouabain 􏰚 2 􏰙M curcumin Ouabain 􏰚 2 􏰙M curcumin 􏰚 10 􏰙M FTC Mitoxantrone alone Mitoxantrone 􏰚 2 􏰙M curcimun Mitoxantrone 􏰚 35 nM gramicidin Mitoxantrone 􏰚 7.5 nM ouabain 6.0􏰟0.9􏰙M 0.2 6.3􏰟0.7􏰙M 0.1 138􏰟16nM 0.1 26􏰟4nM 1E-3 96􏰟15nM 0.7 14􏰟3nM 1.0 6􏰟1nM 1E-2 16􏰟3nM 0.7 206􏰟12nM 1E-4 32􏰟3nM 4E-3 170􏰟4nM 1E-4 187􏰟7nM 1E-4 IC50 HEK-ABCG2 to IC50 from control cellsa HEK-293 control 5.0􏰟0.6􏰙M 5.1􏰟0.6􏰙M 100􏰟22nM 96 􏰟 10 nM 102􏰟16nM 14 􏰟 2 nM 14 􏰟 2 nM 15 􏰟 3 nM 5.6􏰟0.8nM 5.1􏰟0.9nM 5.2􏰟0.6nM 5.3􏰟0.8nM p value of IC50 from HEK-ABCG2 cells relative Relative resistanceb 1.2 􏰟 0.2-fold 1.2 􏰟 0.2-fold 1.4 􏰟 0.3-fold 0.3 􏰟 0.1-fold 1.0 􏰟 0.2-fold 1.0 􏰟 0.3-fold 0.4 􏰟 0.1-fold 1.1 􏰟 0.3-fold 37 􏰟 5.6-fold 6.2 􏰟 1.2-fold 33 􏰟 4.6-fold 35 􏰟 5.5-fold Sensitization/reversal of resistancec 1.0 􏰟 0.2-fold 5.0 􏰟 1.5-fold 1.4 􏰟 0.5-fold 2.5 􏰟 0.9-fold 1.0 􏰟 0.2-fold 6.0 􏰟 2-fold 1.1 􏰟 0.2-fold 1.0 􏰟 0.2-fold a To determine p values, we used a two-tailed Student’s t test based on log(IC50) values. We considered p values 􏰢 0.05 as statistically significant. b Expressed as the ratio between the IC50 value of ABCG2-expressing cells and the IC50 value of control cells. This ratio is the inverse of the selectivity ratio, which is defined as IC50(parental cells)/IC50(MDR cells) (18). c Expressed as the ratio between the relative resistance value of ABCG2-expressing cells in the absence of the second compound and the relative resistance in its presence. In the case of experiments with gA or ouabain, ABCG2-expressing cells are more sensitive to the combined treatment with curcumin than the parental cells (i.e. sensitiza- tion). In the case of experiments with mitoxantrone, the ABCG2-expressing cells are less resistant to combined treatment with curcumin or gA (i.e. reversal of resistance). d Chearwae et al. (26) reported previously that curcumin is presumably not a substrate of ABCG2 transporters. Based on the slight curcumin resistance of ABCG2-expressing HEK cells compared to the parental HEK cells, it appears, however, also possible that the high permeability of curcumin through membranes makes it difficult to detect whether it is transported by ABCG2 transporters or not. In that sense, curcumin may actually be a substrate of ABCG2 transporters, but because of its fast passive back diffusion through mem- branes, it may appear not to be a substrate. We note that in general, net transport observed in transport assays is the sum of passive and active transport processes. incurred sensitivity toward combined exposure to curcumin with either gA or ouabain. These results are therefore on the one hand similar to those reported as CS (reviewed by Pluchino et al. (18) and Szakács et al. (1)), in that resistant cells are more sensitive to certain chemicals than the parental cells. On the other hand, these results are different from previous cases of 31400 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 289 • NUMBER 45 • NOVEMBER 7, 2014

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