Targeting inflammation-driven tumor progression with Zafirlukast via modulation of Jagged-1/Notch-1/Hes-1, Wnt-4/β-catenin, and VEGF signaling pathways in mice.

AIM

This study investigated the potential of Zafirlukast, an inhibitor of cysteinyl leukotriene receptors, to suppress the progression of Solid Ehrlich Carcinoma (SEC) by modulating inflammation-driven oncogenic pathways, with a particular focus on the inhibition of the Jagged-1/Notch-1/Hes-1 and Wnt-4/β-catenin signaling pathways.

METHODS

Fifty female Swiss albino mice were randomly assigned to one control group and four SEC-bearing groups. Zafirlukast was given orally at daily doses of 5 mg/kg and 10 mg/kg for two weeks, while doxorubicin (DOX) was administered intraperitoneally at 5 mg/kg, three times a week for two weeks. Tumor volume and weight were assessed, and hematological, histopathological, immunohistochemical, and molecular markers were analyzed using western blot, RT-PCR, and ELISA.

RESULTS

Zafirlukast markedly reduced tumor volume and mass, with the most pronounced effect observed at the 10 mg/kg dose, by modulating inflammation-driven oncogenic pathways and restoring hematological abnormalities. Treatment with Zaf significantly reduced proinflammatory cytokines (NF-κB, IL-6, TNF-α, iNOS), oxidative stress, and angiogenic mediators (VEGF, MMP-2, MMP-9) (p < 0.01). Furthermore, it downregulated proliferation markers (Cyclin D1, PCNA) and activated pro-apoptotic signaling pathways (Tp53, Bax, Caspase-3) (p < 0.01). RT-PCR analysis confirmed the downregulation of oncogenic genes including DLL4, Jagged-1, Notch-1, Hes-1, Wnt-4, GSK3β, and β-catenin (p < 0.01). Histopathological examination revealed areas of necrosis, reduced neovascularization, and decreased tumor cell proliferation in the treated groups.

CONCLUSION

Zafirlukast exhibits potent anti-tumor activity by targeting multiple oncogenic pathways, highlighting its potential as a therapeutic option for solid tumors and warranting further clinical investigation.