Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation

Abstract

Background:Targeting both mitochondrial bioenergetics and glycolysis pathway is an effective way to inhibit proliferation of tumour cells, including those that are resistant to conventional chemotherapeutics.Methods:In this study, using the Seahorse 96-well Extracellular Flux Analyzer, we mapped the two intrinsic cellular bioenergetic parameters, oxygen consumption rate and proton production rate in six different pancreatic cancer cell lines and determined their differential sensitivity to mitochondrial and glycolytic inhibitors.Results:There exists a very close relationship among intracellular bioenergetic parameters, depletion of ATP and anti-proliferative effects (inhibition of colony-forming ability) in pancreatic cancer cells derived from different genetic backgrounds treated with the glycolytic inhibitor, 2-deoxyglucose (2-DG). The most glycolytic pancreatic cancer cell line was exquisitely sensitive to 2-DG, whereas the least glycolytic pancreatic cancer cell was resistant to 2-DG. However, when combined with metformin, inhibitor of mitochondrial respiration and activator of AMP-activated protein kinase, 2-DG synergistically enhanced ATP depletion and inhibited cell proliferation even in poorly glycolytic, 2-DG-resistant pancreatic cancer cell line. Furthermore, treatment with conventional chemotherapeutic drugs (e.g., gemcitabine and doxorubicin) or COX-2 inhibitor, celecoxib, sensitised the cells to 2-DG treatment.Conclusions:Detailed profiling of cellular bioenergetics can provide new insight into the design of therapeutic strategies for inhibiting pancreatic cancer cell metabolism and proliferation.

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

“…Because cancer cells are more dependent on glycolysis (Warburg effect), 25 there have been various attempts to block glycolysis as a strategy for inhibiting cancer cells. 8,26 A number of drugs that target mitochondrial oxidative phosphorylation in the tricarboxylic acid cycle, such as AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), oxaloacetate, oligomycin, and metformin, have also been extensively tested. 27,28 In our study, rather than using specific GBM cell lines, we chose GBM-TS, as we believe new therapeutic approaches should target the subpopulation of GBM cells responsible for treatment failure.…”

“…1 Modulation of cancer cell metabolism, one of the emerging therapeutic targets proposed to overcome this limitation, is considered a promising therapeutic approach. 7 2-Deoxyglucose (2DG), which is closely related to cellular energy restriction, has been shown to inhibit cancer cell proliferation in pancreatic cancer 8 and breast cancer cell models. 9 Moreover, it has been reported that 2DG becomes a more effective anticancer agent when combined with biguanide, which inhibits mitochondrial oxidative phosphorylation.…”

“…[18][19][20] Many studies have shown that inhibition of either glycolysis or oxidative phosphorylation is effective to decrease proliferation and invasion of cancer cells. [21][22][23] However, exploiting the idea that simultaneous inhibition of multiple metabolic pathways might be a more effective cancer treatment, several researchers have shown that deprivation of tumor bioenergetics through inhibition of multiple energy pathways could be an effective new therapeutic approach for various human tumors 8,24 -an idea that has not been fully evaluated in a GBM-TS model. Here, we tested the hypothesis that dual inhibition of glycolysis and oxidative phosphorylation effectively and synergistically suppresses GBM-TS in a synergetic manner by evaluating the effect of combined treatment with 2DG and metformin on GBM-TS.…”

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

“…An enhanced antioxidant capacity allows cancer cells to not a universal finding, and mitochondrial respiration impairment is not a fixed feature of cancer cells [41] . Although the glycolytic inhibitors targeting the Warburg effect have been investigated in various cancer types, the glycolytic inhibitors with the exception of 3-BP (a lactate analog) [18,19, , 3-BrOP (a 3-bromopyruvate derivative) [71][72][73][74] , and dichloroacetate (DCA) have demonstrated low efficacy in arresting tumor growth when used alone [99] ; these inhibitors include 2-deoxy-D-glucose (a glucose analog) [70,[100][101][102][103][104][105][106][107][108][109][110][111][112] , lonidamine (a derivative of indazole-3-carboxylic acid) [113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132] , methyl jasmonate on HK , 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one on PFK [162]…”

Bioenergetic adaptations in chemo-resistant ovarian cancer cells

“…Bioenergetic characterization of ovarian cancer cells isolated from the tumor or ascites of chemonaïve ovarian cancer patients also revealed a similar picture, confirming the presence of a metabolic heterogeneity in ovarian cancer. Variability in the bioenergetics profiles has been described in breast, sarcoma and pancreatic cancer cell lines 31,40 . A recent analysis by Dier et al of the bioenergetic dynamics and histology of 8 ovarian cancer cell lines also showed a diversity in the energy dynamics, similar to our findings.…”