ABSTRACT Colitis‐associated colorectal neoplasia is the third most life‐threatening consequence of prolonged ulcerative colitis. In the present investigation, we evaluated the efficacy of PARP‐1 inhibitors, 3‐aminobenzamide and Olaparib, in a rodent model of colitis‐associated colorectal cancer (CACC) induced by azoxymethane (AOM) and Dextran sulphate sodium (DSS). For model induction, male BALB/c mice were provided DSS (3% w/v) in three cycles within drinking water following an injection of AOM (10 mg/kg, intraperitoneally). A week after the DSS treatment, 3‐aminobenzamide (5, 10 and 20 mg/kg; i.p.) and Olaparib (10 mg/kg; orally) were given until sacrifice. PARP inhibitors reduced tumour progression by down‐regulating mRNA expression for inflammatory markers, PARP‐1, NLRP3, ASC, Caspase‐1, and TNF‐α. Immunoblotting showed modulation of beclin‐1 expression, while transmission electron microscopy results revealed an increase in autophagosome numbers within tumour tissues. Immunofluorescence for Ki67 and immunoblotting of PCNA indicated elevated cell proliferation in the AOM/DSS group, mitigated by the treatment with 3‐aminobenzamide (20 mg/kg) and Olaparib (10 mg/kg). Finally, DNA damage was also reduced by the intervention of 3‐aminobenzamide and Olaparib as indicated by decrease γH2AX expression. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and β‐catenin expression suggested decrease apoptosis within tumour tissue. Both 3‐aminobenzamide (20 mg/kg; i.p.) and Olaparib (10 mg/kg; orally) exhibited coloprotective effects by modulating PARP‐1‐NLRP3 inflammasome and autophagy pathways in a model of colitis‐associated colorectal cancer.
Singla et al. (Thu,) studied this question.