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Drug Combinations Evoke Collateral Sensitivity against ABCG2 TABLE 4 Effect of rotenone or antimycin A on the viability, relative resistance, and reversal of resistance of HEK-ABCG2 and parental cells IC50 Compound Rotenone alone Rotenone 2 M curcumin 35 nM gA Rotenone 2 M curcumin 7.5 nM ouabain Antimycin A alone Antimycin A 2 M curcumin 35 nM gA Antimycin A 2 M curcumin 7.5 nM ouabain HEK-293 control 6.9 1.8 nM 9.3 3.4 nM 6.4 1.9 nM 6.0 2.1 mM 1.6 0.7 mM 2.0 1.0 mM HEK-ABCG2 4.6 1.6 nM 4.4 1.5 nM 4.5 1.4 nM 4.0 2.0 mM 1.3 0.4 mM 1.8 1.0 mM Relative resistancea 0.7 0.3-fold 0.5 0.2-fold 0.7 0.3-fold 0.7 0.3-fold 0.8 0.4-fold 0.9 0.6-fold Sensitization/reversal of resistanceb 1.4 0.9-fold 0.9 0.6-fold 0.8 0.6-fold 0.8 0.7-fold a Expressed as the ratio of the IC50 value of ABCG2-expressing cells to that of the control cells. b Expressed as the ratio of the relative resistance value of ABCG2-expressing cells in the absence of the second compound to the relative resistance in its presence. FIGURE 8. Sensitivity of HEK-293 control and HEK-ABCG2 cells to inhibitors of the electron transport chain. A, toxicity of increasing concentrations of rotenone on HEK-ABCG2 (red) and parental cells (black) in the absence (solid curve) or presence of 2 M curcumin and 35 nM gA (dashed curve). B, toxicity of increasing concentrations of rotenone on HEK-ABCG2 (red) and parental cells (black) in the absence (solid curve) or presence of 2 M curcumin and 7.5 nM ouabain (dashed curve). C, toxicity of increasing concentrations of antimycin A on HEK-ABCG2 (red) and parental cells (black) in the absence (solid curve) or presence of 2 M curcumin and 35 nM gA (dashed curve). D, toxicity of increasing concentrations of antimycin A on HEK-ABCG2 (red) and parental cells (black) in the absence (solid curve) or presence of 2 M curcumin and 7.5 nM ouabain (dashed curve). The open symbols in C and D indicate that antimycin was not soluble at this concentration. These points were not included in the best curve fits. Motivated by these results, we investigated the effect of rote- none and antimycin A on HEK-ABCG2 and parental cells in the presence and absence of curcumin and gA or curcumin and ouabain. HEK-ABCG2 cells were slightly more sensitive to rotentone and antimycin A than the parental cells (SR 1.5 for both compounds and therefore not significant). Interestingly, however, administration of rotenone or antimycin A did not lead to a significant increase in CS of HEK-ABCG2 cells that were also exposed to curcumin and gA or to curcumin and ouabain (Table 4 and Fig. 8). These experiments also indicated that rotenone and antimycin A were not substrates of ABCG2 transporters (Table 4) in the sense that ABCG2-expressing cells did not incur resistance against these compounds. The absence of a significant effect by rotenone and antimycin A indicated that ROS-mediated toxicity was insufficient to amplify CS toward the drug combinations in HEK-ABCG2 cells. Hence, mechanisms other than ROS-induced apoptosis may be involved in the selective cell death of these cells in response to intracellular ATP depletion by a combination of curcumin with gA or ouabain. Selective Cell Death Occurs through Caspase-dependent Apoptosis—In a landmark paper, Leist et al. (15) showed that the intracellular ATP concentration acts as a switch between apoptosis and necrosis. At ATP concentrations significantly above 50% of basal levels, cell death by apoptosis is favored, whereas ATP concentrations below 50% trigger necrosis. In fact, caspase activation in the apoptotic pathway requires ATP, such that low ATP levels inhibit apoptosis (53). Because com- bined treatments with curcumin and gA or curcumin and oua- bain lowered intracellular ATP in HEK-ABCG2 cells to levels close to the 50% threshold (Fig. 6), it was unclear whether ATP depletion causes selective cell death of HEK-ABCG2 cells over parental cells through apoptosis or necrosis. NOVEMBER 7, 2014 • VOLUME 289 • NUMBER 45 JOURNAL OF BIOLOGICAL CHEMISTRY 31405PDF Image | Curcumin with Either Gramicidin or Ouabain
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