High glucose-induced resistance to 5-fluorouracil in pancreatic cancer cells alleviated by 2-deoxy-D-glucose

Abstract

Abnormal glucose metabolism from hyperglycemia or diabetes aggravates the progression of pancreatic cancer. It is unknown whether high glucose has an impact on the antitumor effect of 5-fluorouracil (5-Fu) and whether targeting aberrant glucose metabolism using 2-deoxy-D-glucose (2-DG) may reverse this effect in high-glucose microenvironments. The cell viability of AsPC-1 and Panc-1 was analyzed by MTT assay following 5-Fu treatment at different glucose concentrations. Altered sensitivity to 5-Fu by 2-DG was also analyzed. LY294002 was used to inhibit PI3K-Akt signaling to determine the mechanism involved. In response to glucose, 5-Fu-induced cell growth inhibition was attenuated in a dose-dependent manner, accompanied with activated p-Akt, while 2-DG enhanced 5-Fu-induced cell growth inhibition. Moreover, blocking the PI3K/Akt pathway by LY294002 effectively eliminated 2-DG-induced apoptosis. In conclusion, high glucose weakens the antitumor effect of 5-Fu via PI3KAkt signaling. Using 2-DG in combination with 5-Fu significantly increased their therapeutic effectiveness in high-glucose microenvironments.

2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents

“…Valera et al [64] found that a non-toxic 5 mM 2-DG concentration sensitizes bladder cancer cells to doxorubicin, cisplatin, and gemcitabine, but not mitomycin C or 5 fluorouracil (5-FU). However, in a pancreatic tumor model, 2-DG was able to sensitize cells to 5-FU, indicating a cell-specific effect [73].…”

“…Due to its ability to inhibit glycolysis and ATP synthesis, disrupt N-glycosylation of proteins, decrease energy metabolism and NADPH levels, and interfere with cellular thiol metabolism, generating oxidative stress, 2-DG appears to be an efficient cytotoxic agent. Importantly, all of these effects are mostly observed in cancer cells, without significant effect on the viability of normal cells [73]. Moreover, a unique ability to affect cancer cells under hypoxic conditions, which often limits traditional cytotoxic agents, has made 2-DG a promising candidate not only for monotherapy, but also as a component of combination therapy with other commercially available drugs, bioactive compounds, and radiotherapy.…”

“…Bevacizumab -GBM [112] 5 -Fluorouracil -pancreatic cancer [73] Trastuzumab -breast cancer [113] Ferulic acid with irradiation -non-small cell lung carcinoma [114] Radiotherapy -breast cancer [ Despite the numerous preclinical and clinical studies cited above, the use of 2-DG in cancer treatment is still limited. Its rapid metabolism and short half-life (according to Hansen et al, after infusion of 50 mg/kg 2-DG, its plasma half-life was only 48 min [117]) make 2-DG a rather poor drug candidate.…”

Active fraction of clove induces apoptosis via PI3K/Akt/mTOR-mediated autophagy in human colorectal cancer HCT-116 cells

“…5B). LY294002 is a well-characterized inhibitor of PI3K (40), and the effect of combined AFC (100 µg/ml) and LY294002 (10 µM) on the expression of p-Akt/Akt and p-mTOR/mTOR on HCT-116 cells was investigated by western blotting. The results revealed that the combination of AFC and LY294002 treatment was more effective in decreasing of the ratios of p-Akt/Akt (P<0.001) and p-mTOR/mTOR (P<0.05) compared with AFC or LY294002 alone ( Fig.…”

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]…”