Abstract
Colitis-associated colorectal cancer (CACC) is one of the devastating complications of long-term inflammatory bowel disease and is associated with substantial morbidity and mortality. Combination of azoxymethane (AOM) and dextran sulfate sodium (DSS) has been extensively used for inflammation-mediated colon tumor development due to its reproducibility, potency, histological and molecular changes, and resemblance to human CACC. In the tumor microenvironment and extra-intestinal tissues, PARP-1, NLRP3 inflammasome, and autophagy’s biological functions are complicated and encompass intricate interactions between these molecular components. The focus of the present investigation is to determine the colonic and extra-intestinal tissue damage induced by AOM-DSS and related molecular mechanisms. Azoxymethane (10 mg/kg, i.p.; single injection) followed by DSS (3 cycles, 7 days per cycle) over a period of 10 weeks induced colitis-associated colon cancer in male BALB/c mice. By initiating carcinogenesis with a single injection of azoxymethane (AOM) and then establishing inflammation with dextran sulfate sodium (DSS), a two-stage murine model for CACC was developed. Biochemical parameters, ELISA, histopathological and immunohistochemical analysis, and western blotting have been performed to evaluate the colonic, hepatic, testicular and pancreatic damage. In addition, the AOM/DSS-induced damage has been assessed by analyzing the expression of a variety of molecular targets, including proliferating cell nuclear antigen (PCNA), interleukin-10 (IL-10), AMP-activated protein kinase (AMPK), poly (ADP-ribose) polymerase-1 (PARP-1), cysteine-associated protein kinase-1 (caspase-1), NLR family pyrin domain containing 3 (NLRP3), beclin-1, and interleukin-1β (IL-1β). Present findings revealed that AOM/DSS developed tumors in colon tissue followed by extra-intestinal hepatic, testicular, and pancreatic damages.
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The authors are thankful to the National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar (Vide no. NPLC-GBJ-2021-2022), and Department of Science and Technology (DST), New Delhi (SERB File Number: CRG/2020/000412), for providing financial support to perform the experiment work related to the present study.
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S.S. conceived and conducted the experiments, analyzed the data, and wrote the manuscript. G.B.J. conceived the idea, reviewed the manuscript, and administered the project. Finally, both the authors have read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Singla, S., Jena, G. Studies on the mechanism of local and extra-intestinal tissue manifestations in AOM-DSS-induced carcinogenesis in BALB/c mice: role of PARP-1, NLRP3, and autophagy. Naunyn-Schmiedeberg's Arch Pharmacol (2023). https://doi.org/10.1007/s00210-023-02878-8
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DOI: https://doi.org/10.1007/s00210-023-02878-8