Dichloroacetate affects proliferation but not survival of human colorectal cancer cells

Abstract

Dichloroacetate (DCA) is a metabolic reprogramming agent that reverses the Warburg effect, causing cancer cells to couple glycolysis to oxidative phosphorylation. This has been shown to induce apoptosis and reduce the growth of various types of cancer but not normal cells. Colorectal cancer cells HCT116, HCT116 p53(-/-), and HCT116 Bax(-/-), were treated with DCA in vitro. Response to treatment was determined by measuring PDH phosphorylation, apoptosis, proliferation, and cell cycle. Molecular changes associated with these responses were determined using western immunoblotting and quantitative PCR. Treatment with 20 mM DCA did not increase apoptosis, despite decreasing levels of anti-apoptotic protein Mcl-1 after 6 h, in any of the cell lines observed. Mcl-1 expression was stabilized with MG-132, an inhibitor of proteasomal degradation. A decrease in Mcl-1 correlated with a decrease in proliferation, both of which showed dose-dependence in DCA treated cells. Cells showed nuclear localization of Mcl-1, however cell cycle was unaffected by DCA treatment. These data suggest that a reduction in the prosurvival Bcl-2 family member Mcl-1 due to increased proteasomal degradation is correlated with the ability of DCA to reduce proliferation of HCT116 human colorectal cancer cells without causing apoptosis.

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

“…Our previous study demonstrated that dichloroacetate effectively induced a dose-dependent proliferation arrest of in vitro cultures of glioblastoma cells but had no significant effect on noncancerous cells (15). This result is in line with most of the studies that investigated the efficacy of dichloroacetate demonstrating that a therapeutic window exists although suprapharmacologic level of dichloroacetate (5-50 mmol/L) is necessary to halt the growth of cancer cells in vitro (9,32,33,35). In the current study, we further analyzed the cell-cycle distribution after dichloroacetate treatment showing that dichloroacetate induced G 2 -M arrest and decreased the cell proportion in S-phase.…”

“…It has been demonstrated with moderate antitumor activity (31)(32)(33) and to induce apoptosis in tumors of patients with glioblastoma by restoring the mitochondrial activity (34). Several studies have also used it as a radiosensitizer in lung (11), colorectal (13), and prostate cancer cells (12) in vitro.…”

Crosstalk among proteome, acetylome and succinylome in colon cancer HCT116 cell treated with sodium dichloroacetate

“…4A) showed that increased proteins involved in structural constituent of ribosome, structural molecule activity, ATPase activity were changed significantly, while the decreased proteins participated in nucleic acid binding, heterocyclic compound binding, and other bindings were severely affected. The results were consistent with the notion that DCA can lead to the inhibition of cell proliferation and cause cell death24. In cellular compartment (Fig.…”

Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies

“…In the colorectal cancer cell line HCT116, DCA has been shown to affect cell proliferation without affecting survival or inducing apoptosis [65]. In other cancer cell lines, the effects were more varied [66].…”