RESUMO
Novel, effective and safe agents are needed for the chemoprevention of colorectal cancer (CRC). This study investigated the effects of chitosan oligosaccharides (COS) on CRC progression and their underlying mechanisms and safety profiles in mice. Using a mouse model of colitis-associated CRC, we found that oral administration of COS (500mg/kg/day) resulted in a â¼60% reduction of tumor size and tumor numbers/sectioning. In addition, COS treatment increased AMPK activity, suppressed the NF-κB-mediated inflammatory response and reduced the expressions of cyclin D1, phosphorylated ribosomal protein S6, and MMP-9 in the colon tissues of these mice. Importantly, administration of COS (500mg/kg/day; 50 days) had no adverse effects on renal or liver functions. Our results indicate that COS suppressed CRC progression via AMPK activation and the suppression of NF-κB and mTOR signaling. COS may be of potential utility in the chemoprevention of CRC.
Assuntos
Anticarcinógenos/farmacologia , Anticarcinógenos/uso terapêutico , Quitosana/química , Neoplasias Colorretais/tratamento farmacológico , Oligossacarídeos/farmacologia , Oligossacarídeos/uso terapêutico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Colite/complicações , Colite/metabolismo , Colite/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ciclina D1/metabolismo , Modelos Animais de Doenças , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
Chitosan oligosaccharide (COS), a biomaterial derived from chitin, is absorbed by intestinal epithelia without degradation and has diverse biological activities including intestinal epithelial function. However, the mode of action is still unclear. This study aimed to investigate the effect of COS on AMP-activated protein kinase (AMPK) in intestinal epithelial cells (IEC) and its potential applications in the intestinal diseases benefited from AMPK activation. COS with molecular weights (MW) from 5,000Da to 14,000Da induced AMPK activation in T84 cells. That with MW of 5,000-Da was the most potent polymer and was used in the subsequent experiments. COS also activated AMPK in other IEC including HT-29 and Caco-2 cells. Mechanism of COS-induced AMPK activation in T84 cells involves calcium-sensing receptor (CaSR)-phospholipase C (PLC)-IP3 receptor channel-mediated calcium release from endoplasmic reticulum (ER). In addition, COS promoted tight junction assembly in T84 cells in an AMPK-dependent manner. COS also inhibited NF-κB transcriptional activity and NF-κB-mediated inflammatory response and barrier disruption via AMPK-independent mechanisms. Interestingly, luminal exposure to COS suppressed cholera toxin-induced intestinal fluid secretion by â¼30% concurrent with AMPK activation in a mouse closed loop model. Importantly, oral administration of COS prevented the development of aberrant crypt foci in a mouse model of colitis-associated colorectal cancer (CRC) via a mechanism involving AMPK activation-induced ß-catenin suppression and caspase-3 activation. Collectively, this study reveals a novel action of COS in activating AMPK via CaSR-PLC-IP3 receptor channel-mediated calcium release from ER. COS may be beneficial in the treatment of secretory diarrheas and CRC chemoprevention.