Hedgehog signaling mastery: R51211's promise in augmenting the therapeutic efficacy of sorafenib

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Hasan A.M.; Cavalu S.; Saber S.; Doghish A.S.; Hamad R.S.; Abdel-Reheim M.A.; Alghamdi M.; Alamri M.M.S.; Alfaifi J.; Adam M.I.E.; Alqarni A.A.; Rezigalla A.A.; Negm S.; El-kott A.F.; Alshehri A.S.; BinAfeef S.F.; Abdel-Ghany S.; Attia M.A.; Mohammed O.A.

Journal: Life Sciences

Publisher: Elsevier Inc.

Publication Date: August 2024

Volume / Issue: Volume 351

Article No.: 122791

ISSN: 243205

DOI: 10.1016/j.lfs.2024.122791

Scopus: View on Scopus

PubMed: 38848936

Document Type: Article

Access: All Open Access; Hybrid Gold Open Access

Authors and Affiliations

Hasan A.M., Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, Oradea, 410087, Romania; Cavalu S., Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, Oradea, 410087, Romania; Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Doghish A.S., Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt, Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, 11231, Egypt; Hamad R.S., Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, 31982, Saudi Arabia, Central Laboratory, Theodor Bilharz Research Institute, Giza, 12411, Egypt; Abdel-Reheim M.A., Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Aldawadmi, 11961, Saudi Arabia, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, 62521, Egypt; Alghamdi M., Department of Internal Medicine, Division of Rheumatology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia; Alamri M.M.S., Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia; Alfaifi J., Department of Child Health, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia; Adam M.I.E., Department of Medical Education and Internal Medicine, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia; Alqarni A.A., Department of Internal Medicine, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia; Rezigalla A.A., Department of Anatomy, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia; Negm S., Department of Life Sciences, College of Science and Art Mahyel Aseer, King Khalid University, Abha, 62529, Saudi Arabia; El-kott A.F., Department of Biology, College of Science, King Khalid University, Abha, 61421, Saudi Arabia, Department of Zoology, Faculty of Science, Damanhour University, Damanhour, 22511, Egypt; Alshehri A.S., Department of Biology, College of Science, King Khalid University, Abha, 61421, Saudi Arabia; BinAfeef S.F., Department of Obstetrics and Gynecology, College of Medicine, Umm Al-Qura University, Makkah, 21421, Saudi Arabia; Abdel-Ghany S., Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt, Department of Basic Medical Sciences, Ibn Sina University for Medical Sciences, Amman, 16197, Jordan; Attia M.A., Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt, Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Diriyiah, Riyadh, 13713, Saudi Arabia; Mohammed O.A., Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, 11566, Egypt, Department of Pharmacology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia

Abstract

Sorafenib is a multikinase inhibitor employed for managing hepatocellular carcinoma (HCC). The emergence of sorafenib resistance presents an obstacle to its therapeutic efficacy. One notable approach to overcoming sorafenib resistance is the exploration of combination therapies. The role of hedgehog signaling in sorafenib resistance has been also examined in HCC. R51211, known as itraconazole, has been safely employed in clinical practice. Through in vitro and in vivo investigations, we assessed the potential of R51211 to enhance the therapeutic efficacy of sorafenib by inhibiting the hedgehog signaling. The zero-interaction potency synergy model demonstrated a synergistic interaction between R51211 and sorafenib, a phenomenon reversed by the action of a smoothened receptor agonist. This dual therapy exhibited an increased capacity to induce apoptosis, as evidenced by alterations in the Bax/BCL-2 ratio and caspase-3, along with a propensity to promote autophagy, as indicated by changes in BECN1, p62, and the LC3I/LC3II ratio. Furthermore, the combination therapy resulted in significant reductions in biomarkers associated with liver preneoplastic alterations, improved liver microstructure, and mitigated changes in liver function enzymes. The substantial decrease in hedgehog components (Shh, SMO, GLI1, and GLI2) following R51211 treatment appears to be a key factor contributing to the increased efficacy of sorafenib. In conclusion, our study highlights the potential of R51211 as an adjunct to sorafenib, introducing a new dimension to this combination therapy through the modulation of the hedgehog signaling pathway. Further investigations are essential to validate the therapeutic efficacy of this combined approach in inhibiting the development of liver cancer. © 2024 The Authors

Keywords

Diethylnitrosamine; Hedgehog signaling; Preneoplastic alterations; R51211/itraconazole; Sorafenib; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Hedgehog Proteins; Humans; Itraconazole; Liver Neoplasms; Male; Mice; Signal Transduction; Xenograft Model Antitumor Assays; alanine aminotransferase; aspartate aminotransferase; beclin 1; caspase 3; gamma glutamyltransferase; lactate dehydrogenase; protein Bax; protein bcl 2; protein Patched 1; R51211; reactive oxygen metabolite; sequestosome 1; thioacetamide; unclassified drug; antineoplastic agent; sonic hedgehog protein; animal cell; animal experiment; Article; cytotoxicity; human; human cell; liver cancer; mRNA expression level; nonhuman; rat; real time polymerase chain reaction; Western blotting; animal; drug effect; drug potentiation; drug resistance; drug screening; drug therapy; liver cell carcinoma; liver tumor; metabolism; mouse; pathology; tumor cell line

Citation Information

Scopus Citations: 1

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