Inhibition of IRE1 RNase activity modulates tumor cell progression and enhances the response to chemotherapy in colorectal cancer.

Drug resistance is one of the clinical challenges that limits the effectiveness of chemotherapy. Recent reports suggest that the unfolded protein response (UPR) and endoplasmic reticulum stress-adaptation signalling pathway, along with increased activation of its inositol-requiring enzyme 1α (IRE1α) arm, may be contributors to the pathogenesis of colorectal cancer (CRC). Here, we aimed to target the IRE1α/XBP1 pathway in order to sensitise CRC cells to the effects of chemotherapy. The CT26 colorectal cell line was treated with tunicamycin, and then was exposed to different concentrations of 5-fluorouracil (5-FU), either alone and/or in combination with the IRE1α inhibitor, 4µ8C. An MTT assay, flow cytometry and RT-PCR were performed to determine cell growth, apoptosis and IRE1α activity, respectively. In vivo BALB/c syngeneic colorectal mice received chemotherapeutic drugs. Treatment responses, tumour sizes and cytotoxicity were assessed via a range of pathological tests. 4µ8C was found to inhibit the growth of CRC, at a concentration of 10 µg/ml, without detectable cytotoxic effects and also significantly enhanced the cytotoxic potential of 5-FU, in CRC cells. In vivo experiments revealed that 4µ8C, at a concentration of 50 µM/kg prevented tumour growth without any cytotoxic or metastatic effects. Interestingly, the combination of 4µ8C with 5-FU remarkably enhanced drug responses, up to 40-60% and also lead to significantly greater inhibition of tumour growth, in comparison to monotherapy, in CRC mice. Targeting the IRE1α/XBP1 axis of the UPR could enhance the effectiveness of chemotherapy in both in vitro and in vivo models of CRC.

Evaluation of the serum prooxidant-antioxidant balance before and after vitamin D supplementation in adolescent Iranian girls.

PURPOSE: Oxidative stress is caused by an imbalance between the antioxidant defenses and pro-oxidant production in favor of pro-oxidant production. Vitamin D has the potential for both pro- and anti-oxidative effects. The aim of this study was to assess the effect of high dose vitamin D supplementation on the prooxidant-antioxidant balance (PAB) in Iranian girls attending High School. MATERIALS AND METHODS: A total of 464 girls aged 12-18 years were asked to take vitamin D capsules containing 50000IU vitamin D3 once a week for a period of 9 weeks. All variables were determined at baseline and after 9 weeks of intervention. Fasting blood samples were taken from all subjects. The serum levels of 25OHD were measured using an electrochemiluminescence method. Serum PAB levels were determined using an ELISA reader at a wavelength of 450 nm. RESULTS: Vitamin D supplementation was associated with an increase in serum PAB (P < 0.001) and a reduction in serum LDL-C (P < 0.001), total cholesterol (P < 0.001) and HDL-C (P < 0.01) serum levels in Iranian adolescent girls. The results obtained from the current study show that there were significant improvements in weight (P < 0.001), BMI (P < 0.001) and FBG (P = 0.02) in adolescent girls who had 50-74.9 nmol/L serum 25OHD levels compared to <50 nmol/L ones after the vitamin D supplementation. There was no significant association between the serum PAB and all biochemical factors (P > 0.05 for all variables). CONCLUSIONS: The results showed that vitamin D supplementation has increased the PAB levels in teenage girls.