Influence of resistance to 5-fluorouracil and tomudex on [18F]‑FDG incorporation, glucose transport and hexokinase activity

Smith, T.

doi:10.3892/ijo.2012.1439

Cited by 4 publications

(1 citation statement)

References 13 publications

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“…Cancer cells escaped 5-FU-induced cell death by entering a quiescent state during cell cycle progression (42). Previous studies have demonstrated that high rates of glucose uptake caused a reduction in 5-FU-induced cytotoxicity (43, 44). Moreover, chemicals that modulate glucose metabolism, such as 3-bromopyruvate, iodoacetate, dichloroacetate, and 2-deoxyglucose, also sensitized cancer cells to 5-FU (45, 46).…”

Section: Introductionmentioning

confidence: 99%

Glucose Metabolites Exert Opposing Roles in Tumor Chemoresistance

Huang

Pai

et al. 2019

Front. Oncol.

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Reprogrammed glucose metabolism and increased glycolysis have been implicated in tumor chemoresistance. The aim was to investigate the distinct roles of the glucose metabolites pyruvate and ATP in chemoresistance mechanisms, including cell death and proliferation. Our data showed higher glucose transporters in colorectal cancer (CRC) from non-responsive patients than those responsive to chemotherapy. Human CRC cell lines exposed to 5-fluorouracil (5-FU) displayed elevated cell viability and larger tumors in xenograft mouse models if cultured in high-glucose medium. Glucose conferred resistance to 5-FU-induced necroptosis via pyruvate scavenging of mitochondrial free radicals, whereas ATP replenishment had no effect on cell death. Glucose attenuated the 5-FU-induced G0/G1 shift but not the S phase arrest. Opposing effects were observed by glucose metabolites; ATP increased while pyruvate decreased the G0/G1 shift. Lastly, 5-FU-induced tumor spheroid destruction was prevented by glucose and pyruvate, but not by ATP. Our finding argues against ATP as the main effector for glucose-mediated chemoresistance and supports a key role of glycolytic pyruvate as an antioxidant for dual modes of action: necroptosis reduction and a cell cycle shift to a quiescent state.

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Section: Introductionmentioning

confidence: 99%

Glucose Metabolites Exert Opposing Roles in Tumor Chemoresistance

Huang

Pai

et al. 2019

Front. Oncol.

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Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway

Yao

Wang

et al. 2016

Tumor Biol.

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Antitumor activity of kaempferol has been studied in various tumor types, but its potency in esophagus squamous cell carcinoma is rarely known. Here, we reported the activity of kaempferol against esophagus squamous cell carcinoma as well as its antitumor mechanisms. Results of cell proliferation and colony formation assay showed that kaempferol substantially inhibited tumor cell proliferation and clone formation in vitro. Flow cytometric analysis demonstrated that tumor cells were induced G0/G1 phase arrest after kaempferol treatment, and the expression of protein involved in cell cycle regulation was dramatically changed. Except the potency on cell proliferation, we also discovered that kaempferol had a significant inhibitory effect against tumor glycolysis. With the downregulation of hexokinase-2, glucose uptake and lactate production in tumor cells were dramatically declined. Mechanism studies revealed kaempferol had a direct effect on epidermal growth factor receptor (EGFR) activity, and along with the inhibition of EGFR, its downstream signaling pathways were also markedly suppressed. Further investigations found that exogenous overexpression of EGFR in tumor cells substantially attenuated glycolysis suppression induced by kaempferol, which implied that EGFR also played an important role in kaempferol-mediated glycolysis inhibition. Finally, the antitumor activity of kaempferol was validated in xenograft model and kaempferol prominently restrained tumor growth in vivo. Meanwhile, dramatic decrease of EGFR activity and hexokinase-2 expression were observed in kaempferol-treated tumor tissue, which confirmed these findings in vitro. Briefly, these studies suggested that kaempferol, or its analogues, may serve as effective candidates for esophagus squamous cell carcinoma management.

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Kaempferol Reverses Aerobic Glycolysis via miR-339-5p-Mediated PKM Alternative Splicing in Colon Cancer Cells

Cui

et al. 2021

J. Agric. Food Chem.

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Colon cancer is an aggressive malignancy with very limited therapeutic approaches. The available therapeutic agents for colon cancer show strong adverse effects and poor effectiveness, indicating the urgent need to identify new therapeutic drugs for this malignancy. Kaempferol, a flavonoid found in a variety of natural foods, exhibits significant inhibitory effects on colon cancer. Here, it was found that kaempferol inhibited the proliferation of human colon cancer cells HCT116 and DLD1 in a dose-dependent manner, and the IC50 values were 63.0 ± 12.9 and 98.3 ± 15.9 μM, respectively. Also, kaempferol treatment delayed G1 phase progression of cell cycle and induced apoptosis. Aerobic glycolysis is the major energy source for various tumor growths, including colon cancer. Indeed, kaempferol treatment impaired glucose consumption, which subsequently led to reduced lactic acid accumulation and ATP production. Mechanistically, kaempferol promoted the expression of miR-339-5p. Further studies identified hnRNPA1 and PTBP1 as two direct targets of miR-339-5p. By directly targeting hnRNPA1 and PTBP1, miR-339-5p reduced the expression of M2-type pyruvate kinase (PKM2) but induced that of PKM1. In conclusion, these data demonstrate that by modulating miR-339-5p-hnRNPA1/PTBP1-PKM2 axis, kaempferol inhibits glycolysis and colon cancer growth, which reveals a new explanation for the molecular mechanism underlying kaempferol anti-tumor.

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Influence of resistance to 5-fluorouracil and tomudex on [18F]‑FDG incorporation, glucose transport and hexokinase activity

Abstract: incorporation is influenced by resistance to antifolate and fluoropyrimidine-based anti-cancer drugs in a drug-dependent manner and the underlying mechanisms appear to be cell-and drug-dependent. Glucose transport may be a useful marker of resistance to 5FU.

Cited by 4 publications

References 13 publications

Glucose Metabolites Exert Opposing Roles in Tumor Chemoresistance

Glucose Metabolites Exert Opposing Roles in Tumor Chemoresistance

Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway

Kaempferol Reverses Aerobic Glycolysis via miR-339-5p-Mediated PKM Alternative Splicing in Colon Cancer Cells

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