Ganciclovir reduces irinotecan-induced intestinal toxicity by inhibiting NLRP3 activation.

Abstract

Delayed diarrhea is a common side effect of irinotecan administration, leading to a reduction in dose and thus a delay in anticancer therapy. Ganciclovir (GCV), an antiretroviral drug, is used to treat cytomegalovirus (CMV) infection. It is unclear whether GCV exhibits protective effects against irinotecan-induced intestinal dysfunction. Intraperitoneal administration of irinotecan with or without GCV for 4days induced intestinal toxicity in mice to analyze diarrhea; beta-glucuronidase (β-GLU) activity; fecal occult blood; hepatic function in blood samples, histopathological changes; and NOD-like receptor 3 (NLRP3), toll-like receptor 4 (TLR4), high-mobility group box 1 protein (HMGB1), phosphorylated nuclear factor kappa B (p-NF-κB), occludin, and zonular occludens (ZO-1) expression in colonic and ileal tissues. In addition, an irinotecan-treated mouse model was constructed and analyzed based on survival time. Expression levels of NLRP3, TLR4, HMGB1, p-NF-κB, occludin, and ZO-1 in normal colonic epithelial cells (NCM460 cells) stimulated with SN-38 were analyzed. GCV treatment reduced various indicators of irinotecan-induced intestinal dysfunction, including delayed-onset diarrhea, pathomorphological changes indicating hepatotoxicity, and proteins related to the HMGB1/TLR4 pathway that induced inflammation; the results were increased body weight, food intake, and expression of the protective proteins occludin and ZO-1. No changes in β-GLU activity were observed. Changes in the expression of proteins related to the HMGB1/TLR4 pathway, occludin, and ZO-1 in SN-38-stimulated NCM460 cells were similar to changes in these proteins in vivo. In addition, administration of GCV improved mouse survival, indicating that the drug had long-term efficacy. Furthermore, GCV + irinotecan did not decrease the anti-tumor effect of irinotecan in vivo. In summary, GCV had intestine-protective and anti-inflammatory properties that possibly reduced irinotecan-induced intestinal dysfunction.