Hyperglycemia Promotes Chemoresistance Through the Reduction of the Mitochondrial DNA Damage, the Bax/Bcl-2 and Bax/Bcl-XL Ratio, and the Cells in Sub-G1 Phase Due to Antitumoral Drugs Induced-Cytotoxicity in Human Colon Adenocarcinoma Cells

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.

Effect of lncRNA‑BC200 on proliferation and migration of liver cancer cells in�vitro and in�vivo

“…Gu et al (34) showed that BC200 can affect the expression of Bax and Bcl-2, suggesting that BC200 is involved in the apoptosis of colorectal cancer (CRC) cells. It has been previously reported that the ratio of Bax/Bcl-xL can be used to measure the level of apoptosis (35). In the present study, following BC200 KO, Bax protein expression was decreased and Bcl-xL protein expression was increased.…”

Type 2 diabetes induced microbiome dysbiosis is associated with therapy resistance in pancreatic adenocarcinoma

“…One of the major challenges is the poor response to the chemotherapeutic drugs. Recent studies have shown that high blood sugar levels can lead to oxaliplatin resistance in patients with Stage III colorectal cancer [33,34]. Similarly, in breast cancer, hyperglycemia induced resistance was observed in the ER+ types [35].…”

Reduced chemotherapeutic sensitivity in high glucose condition: implication of antioxidant response

“…A number of medical conditions can increase blood glucose concentration (hyperglycemia), including diabetes mellitus (DM), obesity, pancreatitis, chronic stress, and cancer [35, 36], and hyperglycemia has been shown to attenuate tumor therapeutic response and to confer resistance to chemotherapy-induced cell death [37, 38]. At molecular level, HG modulates various signaling pathways that control cancer cell proliferation, migration and recurrence [39, 40], as well as apoptosis [27, 39–43]. In our previous studies we showed that HG reduces ADR-induced cell death.…”