The therapeutic potential and deleterious effect of glucocorticoids on AOM/DSS-induced colorectal cancer in mice

Abstract

Background Glucocorticoids (GCs) are widely used in the treatment of various autoimmune and inflammatory diseases, including inflammatory bowel disease (IBD), but the effect of GCs on the development of colitis-associated colorectal cancer (CAC) is largely undefined. Methods We first established azoxymethane and dextran sulfate sodium (AOM/DSS)-induced colorectal cancer and DSS-induced colitis in mice. Dexamethasone (DEX) was then administered at different periods of time to determine its effect on tumorigenesis and tumor progression. Moreover, body weight, stool property and fecal blood of mice were recorded. At the end of the study, the number and load of tumors were evaluated, and the expression of proteins associated with cell proliferation were measured. To evaluate the inflammation in colon, we detected the level of pro-inflammatory cytokine TNFα, and mucosal infiltration of inflammatory cells. Meanwhile, we also assessed the activity of MAPK/JNK pathway. Results AOM injection followed by three cycles of drinking water containing 1.5% DSS successfully induced multiple tumor formation in mouse colon and rectum. Both early and late DEX intervention suppressed tumor growth in mouse colorectum and significantly downregulated the expression of PCNA and cyclin D1. Meanwhile, DEX treatment significantly inhibited the TNFα production, mucosal infiltration of inflammatory cells and the activity of JNK pathway, which was more prominent in mice with early DEX intervention. However, DEX treatment deteriorated the general state of mouse manifested by greater loss of body weight and rectal bleeding. Conclusions Our data conclude that both early and late DEX intervention significantly ameliorate colonic inflammation and inhibit the development of AOM/DSS-induced colorectal cancer, at least partly due to the inhibition of MAPK/JNK pathway. However, the deleterious effect on the general condition of mouse may limit the duration of GCs treatment.

Mangiferin (mango) attenuates AOM-induced colorectal cancer in rat’s colon by augmentation of apoptotic proteins and antioxidant mechanisms

“…The Bax protein as a well-known pro-apoptotic factor increases membrane permeability of the mitochondria and release of cytochrome c, while the β-catenin (an anti-apoptotic factor that preserves outer membrane integrity of the mitochondria) expression in their colon tissues 52 . The β-catenin staining technique is used to assess the level of β-catenin protein expression, which is considered an important regulatory factor to cellular proliferation and aids in T-suppressor cells (aiding in cellular proliferations).The present study showed reduced Bax protein expression and increased β-catenin protein expression in cancer control rats, indicating a significant imbalance between these two proteins could lead to cellular dysfunctionality and changes in the mitochondrial route of apoptosis 53 , 54 . The present MF (30 and 60 mg/kg) supplementation caused significant positive modulation of Bax protein and noticeably reduction of the β-catenin protein appearance in rat’s colon, which could be a molecular mechanism behind lower ACF incidence and the chemoprotective action of MF in AOM-pre-treated rats.…”

Current Strategies and Potential Prospects of Nanomedicine-Mediated Therapy in Inflammatory Bowel Disease

“…Therapies such as 5-aminosalicylic acid, corticosteroids, immunomodulators, antibiotics, and biological agents have been widely offered in IBD treatment, significantly reducing colitis-associated colorectal cancer. [10][11][12] These tools are also defined as effective early preventions. However, immunomodulators may often lead to severe side effects among healthy tissues, such as lymphoma development.…”