Itraconazole halts hepatocellular carcinoma progression by modulating sonic hedgehog signaling in rats: A novel therapeutic approach

Liver cancer stands as the fourth leading global cause of death, and its prognosis remains grim due to the limited effectiveness of current medical interventions. Among the various pathways implicated in the development of hepatocellular carcinoma (HCC), the hedgehog signaling pathway has emerged as...

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Published in:Pathology, research and practice research and practice, 2024-01, Vol.253, p.155086-155086, Article 155086
Main Authors: Mohammed, Osama A, Doghish, Ahmed S, Saleh, Lobna A, Alghamdi, Mushabab, Alamri, Mohannad Mohammad S, Alfaifi, Jaber, Adam, Masoud I E, Alharthi, Muffarah Hamid, Alshahrani, Abdullah M, Alhalafi, Abdullah Hassan, BinAfif, Waad Fuad, Rezigalla, Assad Ali, Abdel-Reheim, Mustafa Ahmed, El-Wakeel, Hend S, Attia, Mohammed A, Elmorsy, Elsayed A, Al-Noshokaty, Tohada M, Nomier, Yousra, Saber, Sameh
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - pathology
Hedgehog Proteins - genetics
Itraconazole - pharmacology
Itraconazole - therapeutic use
Liver Neoplasms - drug therapy
Liver Neoplasms - pathology
Rats
Wnt Signaling Pathway
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Summary:Liver cancer stands as the fourth leading global cause of death, and its prognosis remains grim due to the limited effectiveness of current medical interventions. Among the various pathways implicated in the development of hepatocellular carcinoma (HCC), the hedgehog signaling pathway has emerged as a crucial player. Itraconazole, a relatively safe and cost-effective antifungal medication, has gained attention for its potential as an anticancer agent. Its primary mode of action involves inhibiting the hedgehog pathway, yet its impact on HCC has not been elucidated. The main objective of this study was to investigate the effect of itraconazole on diethylnitrosamine-induced early-stage HCC in rats. Our findings revealed that itraconazole exhibited a multifaceted arsenal against HCC by downregulating the expression of key components of the hedgehog pathway, shh, smoothened (SMO), and GLI family zinc finger 1 (GLI1), and GLI2. Additionally, itraconazole extended survival and improved liver tissue structure, attributed mainly to its inhibitory effects on hedgehog signaling. Besides, itraconazole demonstrated a regulatory effect on Notch1, and Wnt/β-catenin signaling molecules. Consequently, itraconazole displayed diverse anticancer properties, including anti-inflammatory, antiangiogenic, antiproliferative, and apoptotic effects, as well as the potential to induce autophagy. Moreover, itraconazole exhibited a promise to impede the transformation of epithelial cells into a more mesenchymal-like phenotype. Overall, this study emphasizes the significance of targeting the hedgehog pathway with itraconazole as a promising avenue for further exploration in clinical studies related to HCC treatment.
ISSN:0344-0338
1618-0631
DOI:10.1016/j.prp.2023.155086