The immunomodulatory effects of topiramate on azoxymethane-induced colon carcinogenesis in rats: The role of the inflammatory cascade, vascular endothelial growth factor, AKT/mTOR/MAP kinase signaling and the apoptotic markers

• Published in: International immunopharmacology 2021-09, Vol.98, p.107830, Article 107830
• Main Authors: Kabel, Ahmed M., Ashour, Ahmed M., Ali, Dina A., Arab, Hany H.
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; Anticancer properties; Antigens; Antioxidants; Antitumor activity; Apoptosis; Apoptosis - drug effects; Apoptosis - immunology; Azoxymethane; Azoxymethane - administration & dosage; Azoxymethane - toxicity; Body weight; Body weight gain; Cancer; Carcinoembryonic antigen; Carcinogenesis; Carcinogenesis - chemically induced; Carcinogenesis - drug effects; Carcinogenesis - immunology; Carcinogens; Caspase-9; Cellulose; Chemotherapy; Colon; Colon - drug effects; Colon - immunology; Colon - pathology; Colon cancer; Colonic Neoplasms - chemically induced; Colonic Neoplasms - drug therapy; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Colorectal cancer; Cytokines; Drug Screening Assays, Antitumor; Gastrointestinal system; Gastrointestinal tract; Growth factors; Humans; Immunomodulation; Inflammation; Intestinal Mucosa - drug effects; Intestinal Mucosa - immunology; Intestinal Mucosa - pathology; Kinases; Male; MAP kinase; MAP Kinase Signaling System - drug effects; Methylcellulose; Microenvironments; Neoplasms, Experimental - chemically induced; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - immunology; Neoplasms, Experimental - pathology; Nerve growth factor; p38 MAP kinase; Proto-Oncogene Proteins c-akt - metabolism; Rats; Reactive oxygen species; Signaling; Tissues; Topiramate; Topiramate - pharmacology; Topiramate - therapeutic use; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Vascular endothelial growth factor
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.107830

•We investigated the immunomodulatory effects of topiramate on colon carcinogenesis.•Topiramate suppressed oxidative stress & increased Nrf2/HO-1 content.•Topiramate inhibited TGF-β1 expression and decreased IL-10, IL-18 & VEGF levels.•Topiramate inactivated p-AKT/mTOR/MAP kinase & enhanced apoptosis.•Topiramate decreased carcinoembryonic antigen levels and Ki-67 expression. Colon cancer is a malignant condition that affects the lower gastrointestinal tract and has unfavorable prognosis. Its mechanisms range from enhanced production of reactive oxygen species, inflammatory changes in the colon microenvironment and affection of the apoptotic pathways. Due to the high incidence of resistance of colon cancer to the traditional chemotherapeutic agents, a need for finding safe/effective agents that can attenuate the malignant changes had emerged. To investigate the possible immunomodulatory and antitumor effects of topiramate on azoxymethane-induced colon cancer in rats. Fifty male Wistar rats were randomized into five equal groups as follows: Control; azoxymethane-induced colon cancer; azoxymethane + methyl cellulose; azoxymethane + topiramate small dose; and azoxymethane + topiramate large dose. The body weight gain, serum carcinoembryonic antigen (CEA), tissue antioxidant status, proinflammatory cytokines, vascular endothelial growth factor (VEGF), Nrf2/HO-1 content, p-AKT, mTOR, p38 MAP kinase, caspase 9, nerve growth factor beta and beclin-1 were measured. Also, parts of the colon had undergone histopathological and immunohistochemical evaluation. Topiramate improved the body weight gain, decreased serum CEA, augmented the antioxidant defenses in the colonic tissues with significant amelioration of the inflammatory changes, decline in tissue VEGF and p-AKT/mTOR/MAP kinase signaling and increased Nrf2/HO-1 content in a dose-dependent manner when compared to rats treated with azoxymethane alone. In addition, topiramate, in a dose-dependent manner, significantly enhanced apoptosis and improved the histopathological picture in comparison to animals treated with azoxymethane alone. Taking these findings together, topiramate might serve as a new effective adjuvant line of treatment of colon cancer.