Troglitazone Stimulates Cancer Cell Uptake of ¹⁸F-FDG by Suppressing Mitochondrial Respiration and Augments Sensitivity to Glucose Restriction

Abstract

We evaluated how troglitazone influences cancer cell glucose metabolism and uptake of 18 F-FDG, and we investigated its molecular mechanism and relation to the drug's anticancer effect. Methods: Human T47D breast and HCT116 colon cancer cells that had been treated with troglitazone were measured for 18 F-FDG uptake, lactate release, oxygen consumption rate, mitochondrial membrane potential, and intracellular reactive oxygen species. Viable cell content was measured by sulforhodamine-B assays. Results: Treatment with 20 μM troglitazone for 1 h acutely increased 18 F-FDG uptake in multiple breast cancer cell lines, whereas HCT116 cells showed a delayed reaction. In T47D cells, the response occurred in a dose-dependent (threefold increase by 40 μΜ) manner independent of peroxisome proliferator-activated receptor-γ and was accompanied by a twofold increase of lactate production, consistent with enhanced glycolytic flux. Troglitazone-treated cells showed severe reductions of the oxygen consumption rate, indicating suppression of mitochondrial respiration, which was accompanied by significantly decreased mitochondrial membrane potential and increased concentration of reactive oxygen species. Troglitazone dose-dependently reduced T47D and HCT116 cell content, which was significantly potentiated by restriction of glucose availability. In T47D cells, cell reduction closely correlated with the magnitude of increase in relative 18 F-FDG uptake (r 5 0.821, P 5 0.001). Conclusion: Troglitazone stimulates cancer cell uptake of 18 F-FDG through a shift of metabolism toward glycolytic flux, likely as an adaptive response to impaired mitochondrial oxidative respiration.

Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds

“…Unlike the antidiabetic effects of this drug, many other actions of troglitazone are thought to occur in a PPARγ-independent manner. Since troglitazone is known to cause mitochondrial dysfunction, its effect on glucose metabolism was investigated [79]. Troglitazone enhanced uptake of glucose in several breast cancer cell lines, but changes in GLUT levels do not seem to play a role in this effect, that rather appears to involve MAPK, AMPK, and EGFR.…”

The troglitazone derivative EP13 disrupts energy metabolism through respiratory chain complex I inhibition in breast cancer cells and potentiates the antiproliferative effect of glycolysis inhibitors

“…It is well described that TZDs exert direct and rapid effects on mitochondrial respiration [ 31 ]. For instance, mitochondrial respiration inhibition was observed in a few minutes in response to 10 µM TGZ in T47D breast cancer cells and HCT116 colon cancer cells [ 32 ]. In our culture conditions, we did not observe any effect of TGZ on mitochondrial respiration after 4 h of exposure at its IC 50 (or at 50 µM for Hs578T cells) regardless of the cell line.…”

Troglitazone exerts metabolic and antitumor effects on T47D breast cancer cells by suppressing mitochondrial pyruvate availability

“…The selection of T47D cells for our experiments was based on our previous observation that oxidative phosphorylation in T47D cells is strongly suppressed by TGZ treatment (10). This was accompanied by reduced mitochondrial membrane potential and increased reactive oxygen species generation, indicating a perturbation of mitochondrial function.…”

“…The present study investigated the effects of TGZ on cancer cells with divergent sensitivity to 2-DG. T47D cells were investigated, as TGZ was previously observed to exert strong suppressive effects on the mitochondrial function and oxidative phosphorylation of these cells (10). CT26 cells were selected as a cancer cell type exhibiting low TGZ sensitivity based on pilot experiments.…”

“…Recent studies support the repurposing of troglitazone (TGZ) as a promising thiazolidinedione for cancer therapy (9). Our group previously demonstrated that TGZ acutely impairs mitochondrial oxidative respiration in a peroxisome proliferator-activated receptor-γ-independent manner (10). The two pathways for glucose metabolism (i.e., mitochondrial oxidative phosphorylation vs. cytoplasmic lactate production) branch out from pyruvate.…”