Abstract
Diabetes and cancer are common, chronic, and potentially fatal diseases that frequently co-exist. Observational studies clearly indicate that the risk of several types of cancer is increased in diabetic patients and a number of cancer types have shown a higher mortality rate in patients with hyperglycemic associated pathologies. This scenario could be due, at least in part, to a lower efficacy of the cancer treatments which needs to be better investigated. Here, we evaluated the effects of a prolonged exposure to high glucose (HG) to the response to chemotherapy on human colon adenocarcinoma HT29 and LOVO cell lines. We observed that hyperglycemia protected against the decreased cell viability and cytotoxicity and preserved from the mitochondrial DNA lesions induced by doxorubicin (DOX) and 5-fluorouracil (5-FU) treatments by lowering ROS production. In HT29 cells the amount of intracellular DOX and its nuclear localization were not modified by HG incubation in terms of Pgp, BCRP, MRP1, 5 and 8 activity and gene expression. On the contrary, in LOVO cells, the amount of intracellular DOX was significantly decreased after a bolus of DOX in HG condition and the expression and activity of MPR1 was increased, suggesting that HG promotes drug chemoresistance in both HT29 and LOVO cells, but in a different way. In both cell types, HG condition prevented the susceptibility to apoptosis by decreasing the ratio Bax/Bcl-2 and Bax/Bcl-XL and diminished the level of cytosolic cytochrome c and the cleavage of full length of PARP induced by DOX and 5-FU. Finally, hyperglycemia reduced cell death by decreasing the cell percentage in sub-G1 peak induced by DOX (via a cell cycle arrest in the G2/M phase) and 5-FU (via a cell cycle arrest in the S phase) in HT29 and LOVO cells. Taken together, our data showed that a prolonged exposure to HG protects human colon adenocarcinoma cells from the cytotoxic effects of two widely used chemotherapeutic drugs, impairing the effectiveness of the chemotherapy itself.
Highlights
Antineoplastic drugs are an important therapeutic tool for cancer patients, but the development of multidrug resistance (MDR) may result in failure of the treatment, leading to tumor relapse and further progression
The extracellular release of the intracellular enzyme lactate dehydrogenase (LDH), used as an index of cytotoxicity, was significantly lower in HT29 and LOVO cells cultured in high glucose (HG) compared with control cells at the same doses and time incubation of DOX (Figures 1B,D,F,H) or of 5-FU (Figures 2B,D), whereas, in our experimental conditions, hyperglycemia alone did not shown any cytotoxic effect
Garufi and D’ Oraz (2014) has reported that a high blood glucose condition negatively affects tumor response to therapies through the specific inhibition of p53 – Ser 46 phosphorylation reducing p53 apoptotic activity in colon, lung and ovarian cancer cell lines treated with chemotherapeutic agents; Zeng et al (2010) has shown that hyperglycemia reduces the efficacy of chemotherapeutic drugs in malignant breast epithelial cells through the activation of the fatty acid synthase (FAS), enzyme responsible for the de novo synthesis of fatty acids from sugars and the expression of which positively correlates with aggressive tumors and poorer prognoses in various cancers (Kuhajda, 2000)
Summary
Antineoplastic drugs are an important therapeutic tool for cancer patients, but the development of multidrug resistance (MDR) may result in failure of the treatment, leading to tumor relapse and further progression. Hyperglycemia is often a consequence of a Western lifestyle that is associated with metabolic syndrome and type-2 diabetes or obesity, and high levels of glucose may be present in the blood for many years before the onset of overt diabetes (which may not appear at all throughout the life) (Atlas Website, 2014). Hyperglycemia is a pathophysiological condition characterized by high blood glucose concentration that is a key pathological factor involved in diabetic complications (Nathan et al, 2013), and it has been shown to predispose to cancer development (Biadgo et al, 2016) and progression (Duan et al, 2014). It is becoming clear that sustained hyperglycemia is related to cancer incidence (Orgel and Mittelman, 2013), and to cancer response to chemo-radiotherapy treatment (Meyerhardt et al, 2003; Caudle et al, 2008)
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