Thesis (M.Sc.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Purpose: Sonic Hedgehog (SHh) and cyclooxygenase2 (COX2) pathways are involved in growth and progression of many human malignancies, including colorectal cancer (CRC). Evaluation of the potential antitumor effects resulting from co-targeting of both pathways is worthy. Thus, the current study was designed to explore the potential anti-carcinogenic effects resulting from combination of GANT61, a Glioma-associated oncogene homologue (GLI) inhibitor that suppresses the SHh pathway, with celecoxib (CXB), a selective COX2 inhibitor, on the CRC cell line HCT-116. Methods: Determination of IC50, the combination (CI)/concentration reduction indices (CRI) for CRC cell line (HCT-116) treated with different concentrations of GANT61and/or CXB was done. Caspase-3 activity, as well as the relative gene expressions of GLI-1 and COX-2 were assessed. In addition, the protein expressions of cyclin D1, vascular endothelial growth factor (VEGF), pS473-protein kinase B (AKT), pS536- nuclear factor kappa beta (NFmB) p65, COX2, and prostaglandin E2 (PGE2) were evaluated. Results: The synergistic effect between GANT61 and CXB was evidenced by CI which was below 1 with declined CRIs at IC50. CXB not only augmented the GANT61-induced mRNA GLI-1 inhibition but also abated the unexpected COX2 gene protein expression.Moreover, the co-treatment resulted in better downregulation of protein expressions of pS536-NFmB p65, pS473-AKT, and COX2 compared to either single drug groups. Similarly, it proved superior effects on the reduced cyclin D1, VEGF, and PGE2 contentsand the restored caspase-3 activity

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