High blood sugar levels but not diabetes mellitus significantly enhance oxaliplatin chemoresistance in patients with stage III colorectal cancer receiving adjuvant FOLFOX6 chemotherapy

Yang, I‐Ping; Zhang, Miao; Huang, Ching‐Wen; Tsai, Hsiang‐Lin; Yeh, Yung‐Sung; Su, Wei‐Chih; Chang, Tsung‐Kun; Chang, Se-Fen; Wang, Jaw‐Yuan

doi:10.1177/1758835919866964

Cited by 35 publications

(32 citation statements)

References 46 publications

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“…This is well supported by previous studies who have found the same effect when using resazurin 47,48 . The sensitivity of cancer cells to drug treatments in different glucose concentrations is not only relevant for in vitro testing, but also clinically where many patients may present with T2D and elevated blood glucose levels, which has been associated with chemoresistance 49 . Not all cancer cells exhibit Warburg metabolism.…”

Section: Discussionmentioning

confidence: 99%

Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells

Alhourani

Tidwell

Bokil

et al. 2021

Sci Rep

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Cancer cells exhibit altered metabolism, a phenomenon described a century ago by Otto Warburg. However, metabolic drug targeting is considered an underutilized and poorly understood area of cancer therapy. Metformin, a metabolic drug commonly used to treat type 2 diabetes, has been associated with lower cancer incidence, although studies are inconclusive concerning effectiveness of the drug in treatment or cancer prevention. The aim of this study was to determine how glucose concentration influences cancer cells’ response to metformin, highlighting why metformin studies are inconsistent. We used two colorectal cancer cell lines with different growth rates and clinically achievable metformin concentrations. We found that fast growing SW948 are more glycolytic in terms of metabolism, while the slower growing SW1116 are reliant on mitochondrial respiration. Both cell lines show inhibitory growth after metformin treatment under physiological glucose conditions, but not in high glucose conditions. Furthermore, SW1116 converges with SW948 at a more glycolytic phenotype after metformin treatment. This metabolic shift is supported by changed GLUT1 expression. Thus, cells having different metabolic phenotypes, show a clear differential response to metformin treatment based on glucose concentration. This demonstrates the importance of growth conditions for experiments or clinical studies involving metabolic drugs such as metformin.

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Section: Discussionmentioning

confidence: 99%

Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells

Alhourani

Tidwell

Bokil

et al. 2021

Sci Rep

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“…Additionally, GC cells tend to show multidrug resistance and reduced susceptibility to chemotherapy drugs under high glucose conditions [27]. Another study reported that hyperglycemia can enhance oxaliplatin chemoresistance and lead to poor clinical outcomes in stage III colorectal cancer patients receiving adjuvant chemotherapy [28]. This study aimed to investigate the effects of hyperglycemia on the GC malignant phenotype and the underlying mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia promotes Snail-induced epithelial–mesenchymal transition of gastric cancer via activating ENO1 expression

Xu¹,

Chen²,

Zhu³

et al. 2019

Cancer Cell Int

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Background: Gastric cancer (GC) is one of the most common gastrointestinal malignancies worldwide. Emerging evidence indicates that hyperglycemia promotes tumor progression, especially the processes of migration, invasion and epithelial-mesenchymal transition (EMT). However, the underlying mechanisms of GC remain unclear. Method: Data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to detect the expression of glycolysis-related enzymes and EMT-related transcription factors. Small interfering RNA (siRNA) transfection was performed to decrease ENO1 expression. Immunohistochemistry (IHC), Western blot and qRT-PCR analyses were used to measure gene expression at the protein or mRNA level. CCK-8, wound-healing and Transwell assays were used to assess cell proliferation, migration and invasion. Results: Among the glycolysis-related genes, ENO1 was the most significantly upregulated in GC, and its overexpression was correlated with poor prognosis. Hyperglycemia enhanced GC cell proliferation, migration and invasion. ENO1 expression was also upregulated with increasing glucose concentrations. Moreover, decreased ENO1 expression partially reversed the effect of high glucose on the GC malignant phenotype. Snail-induced EMT was promoted by hyperglycemia, and suppressed by ENO1 silencing. Moreover, ENO1 knockdown inhibited the activation of transforming growth factor β (TGF-β) signaling pathway in GC. Conclusions: Our results indicated that hyperglycemia induced ENO1 expression to trigger Snail-induced EMT via the TGF-β/Smad signaling pathway in GC.

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“…This is the first report to demonstrate that blood glucose levels are related to the prognosis of cancer patients on a ketogenic diet. Only one previous report was found in patients with stage III colorectal cancer receiving adjuvant FOLFOX6 [24]. The ketogenic diet is said to affect glucose metabolism [25] and gene expression [26,27] because of changes in the metabolic environment and ketone bodies acting as signal molecules [28].…”

Section: Discussionmentioning

confidence: 99%

Promising Effect of a New Ketogenic Diet Regimen in Patients with Advanced Cancer

et al. 2020

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A ketogenic diet is expected to be an effective support therapy for patients with cancer, but the degree and duration of carbohydrate restriction are unclear. We performed a case series study of a new ketogenic diet regimen in patients with different types of stage IV cancer. Carbohydrates were restricted to 10 g/day during week one, 20 g/day from week two for three months, and 30 g/day thereafter. A total of 55 patients participated in the study, and data from 37 patients administered the ketogenic diet for three months were analyzed. No severe adverse events associated with the diet were observed. Total ketone bodies increased significantly, and both fasting blood sugar and insulin levels were suppressed significantly for three months after completion of the study. Five patients showed a partial response on Positron emission tomography–computed tomography (PET-CT) at three months. Three and seven patients showed complete and partial responses, respectively at one year. Median survival was 32.2 (maximum: 80.1) months, and the three-year survival rate was 44.5%. After three months on the ketogenic diet, the serum Alb, BS, and CRP (ABC) score could be used to stratify the patients into groups with significantly different survival rates (p < 0.001, log-rank test). Our ketogenic diet regimen is considered to be a promising support therapy for patients with different types of advanced cancer.

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High blood sugar levels but not diabetes mellitus significantly enhance oxaliplatin chemoresistance in patients with stage III colorectal cancer receiving adjuvant FOLFOX6 chemotherapy

Cited by 35 publications

References 46 publications

Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells

Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells

Hyperglycemia promotes Snail-induced epithelial–mesenchymal transition of gastric cancer via activating ENO1 expression

Promising Effect of a New Ketogenic Diet Regimen in Patients with Advanced Cancer

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