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.