Silymarin and Zinc Oxide Nanoparticles Attenuate Experimental Colon Cancer in Rats Through Crosstalk of miR-192 and β-Catenin Pathways

Colon cancer (CC) is a leading cause of cancer-related mortality globally. Although chemotherapy remains the primary treatment, its toxicity and drug resistance highlight the need for alternative therapeutic strategies. Silymarin (Sily), a natural compound, and zinc oxide nanoparticles (ZnO-NPs) have shown potential antitumor activity. This study evaluated Sily and/or ZnO-NPs against DMH-induced CC in rats. Thirty male Sprague-Dawley rats were divided into five groups (n = 6): control, CC (DMH 20 mg/kg/16-week S.C.), and three groups receiving Sily (40 mg/kg orally), ZnO-NPs (10 mg/kg IP), or their combination daily for 4 weeks. In comparison to the CC group, Sily or ZnO-NPs significantly decreased CEA levels, restored mucin synthesis, and improved colonic histology, with the combination treatment producing the most pronounced antitumor effects. Treatments attenuated oxidative stress, with Sily restoring SOD and GSH levels, whereas ZnO-NPs primarily reduced lipid peroxidation, as reflected by decreased MDA levels. Mechanistically, the combined therapy decreased inhibitory GSK-3β phosphorylation and β-catenin expression, consistent with restoration of GSK-3β-mediated suppression of β-catenin. The combination also restored PKCα and miR-192 expression and reduced the expression of the proliferation- and metastasis-associated markers MMP-9, c-Myc, and Cyclin-D1. CD133 expression was significantly reduced, suggesting an effect on the cancer stem cell-associated phenotype. Sily and ZnO-NPs demonstrated therapeutic effects against CC, particularly when administered in combination. Their antitumor effects were associated with modulation of miR-192/PKCα and GSK-3β/β-catenin signaling, supporting further investigation of their combined multitargeted potential in CC.