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

Autor: Hasan AM; Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania. Electronic address: alexhasandu@gmail.com., Cavalu S; Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania. Electronic address: simona.cavalu@gmail.com., Saber S; Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt. Electronic address: sameh.saber@deltauniv.edu.eg., Doghish AS; 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. Electronic address: ahmed.soliman2@buc.edu.eg., Hamad RS; Biological Sciences Department, College of Science, King Faisal University, Al Ahsa 31982, Saudi Arabia; Central Laboratory, Theodor Bilharz Research Institute, Giza 12411, Egypt. Electronic address: rhamad@kfu.edu.sa., Abdel-Reheim MA; 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. Electronic address: m.ahmed@su.edu.sa., Alghamdi M; Department of Internal Medicine, Division of Rheumatology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia. Electronic address: mualghamdi@ub.edu.sa., Alamri MMS; Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia. Electronic address: malamri@ub.edu.sa., Alfaifi J; Department of Child Health, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia. Electronic address: jalfaifi@ub.edu.sa., Adam MIE; Department of Medical Education and Internal Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia. Electronic address: mieadam@ub.edu.sa., Alqarni AA; Department of Internal Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia. Electronic address: almohsen@ub.edu.sa., Rezigalla AA; Department of Anatomy, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia. Electronic address: arezigalla@ub.edu.sa., Negm S; Department of Life Sciences, College of Science and Art Mahyel Aseer, King Khalid University, Abha 62529, Saudi Arabia. Electronic address: snsir@kku.edu.sa., El-Kott AF; Department of Biology, College of Science, King Khalid University, 61421 Abha, Saudi Arabia; Department of Zoology, Faculty of Science, Damanhour University, Damanhour 22511, Egypt. Electronic address: elkottaf@yahoo.com., Alshehri AS; Department of Biology, College of Science, King Khalid University, 61421 Abha, Saudi Arabia. Electronic address: ashehri@kku.edu.sa., BinAfeef SF; Department of Obstetrics and Gynecology, College of Medicine, Umm Al-Qura University, Makkah 21421, Saudi Arabia. Electronic address: sfafeef@uqu.edu.sa., 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. Electronic address: samghany@mans.edu.eg., Attia MA; 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. Electronic address: dr_moh_sas@mans.edu.eg., Mohammed OA; 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. Electronic address: osamaabbass@med.asu.edu.eg.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2024 Aug 15; Vol. 351, pp. 122791. Date of Electronic Publication: 2024 Jun 06.
DOI: 10.1016/j.lfs.2024.122791
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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