Metformin promotes the inhibitory effect of 5-Aminosalicylic Acid on inflammation-mediated proliferation and progression of colorectal Cancer cell lines

Abstract

e49 lead to nephrotoxicity and ototoxicity. However, in SDD, tobramycin suspension is given orally and aminoglycosides are not absorbed via the gut. Therefore, SDD will, generally, not lead to systemic exposure. However, we describe a patient with Graft Versus Host Disease (GVHD) who developed toxic tobramycin levels. Methods: In this case report, we describe a 34 year old male patient with Acute Myeloid Leukemia. After allogenic stem cell transplantation he developed GVHD of the intestines, amongst all leading to severe diarrhea. Previously, several ICU patients with SDD and GVHD developed systemic tobramycin exposure. Therefore, tobramycin levels were measured by means of EMIT Immunoassay (Architect, Abbott). Results: After use of 8 times a day 80 mg tobramycin orally for 30 days, his tobramycin trough level was 3.5 mg/L (reference < 0.5 mg/L). His creatinine was 102 μ mol/L and urea was 23.1 mmol/L (increase > 20% last 4 days). Tobramycin was stopped and levels dropped to 0.87 mg/L after 2 days and 0.22 mg/L after 4 days. Tobramycin was started again in a regimen of 4 times a day 80 mg tobramycin orally, under daily monitoring of tobramycin levels. Creatinine and urea recovered. High tobramycin levels were contributed to systemic leakage of tobramycin via the intestines. Conclusion: In SDD, tobramycin is normally not absorbed. However, in severe intestine GVHD, systemic absorption of tobramycin can occur. In this patient toxic tobramycin levels were combined with impaired renal function. In patients with GVHD of the intestines and frequent administration of tobramycin-containing SDD frequent monitoring of tobramycin levels is recommended. Introduction: The link between inflammation and cancer has been suggested and confirmed by the use of anti-inflammatory therapies in cancer prevention and treatment. Five-aminosalicylic acid (5-ASA) was shown to decrease the growth and survival of colorectal cancer (CRC) cells. Metformin, an oral anti-diabetic drug, decreased the incidence of colorectal adenomas in diabetic patients with previous CRC and induced apoptosis in several cancer cell lines. This study addresses the combinatory effect of 5-ASA and Metformin and explores their role on oxidative stress markers, inflammatory mediators, as well as apoptosis on HCT-116 and Caco-2 CRC cell lines. Materials and Methods: Drug interaction was evaluated using isobologram equation and the expression of pro-inflammatory cytokines was determined by RT-PCR. Protein levels of BAX and Bcl-2 was determined using western blotting and matrix metalloproteinases-2 and -9 by zymography. Caspase-3 activity, malondialdehyde (MDA), glutathione (GSH) and nitric oxide contents were measured spectrophotometrically. Results: Metformin enhances CRC cell death induced by 5-ASA, this manifested a significant activation of apoptotic machinery, caspase-3 activity and the BAX/Bcl-2 protein ratio. In addition, the combination resulted in an exaggerated increase in MDA and decrease in intracellular GSH levels indicating an increase in oxidative stress ...