A novel combination therapy targets sonic hedgehog signaling by the dual inhibition of HMG-CoA reductase and HSP90 in rats with non-alcoholic steatohepatitis

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Mohammed O.A.; Youssef M.E.; Doghish A.S.; Hamad R.S.; Abdel-Reheim M.A.; Alghamdi M.; Alamri M.M.S.; Alfaifi J.; Adam M.I.E.; Alharthi M.H.; Alhalafi A.H.; Bahashwan E.; Rezigalla A.A.; BinAfif D.F.; Abdel-Ghany S.; Attia M.A.; Elmorsy E.A.; AL-Noshokaty T.M.; Fikry H.; Saleh L.A.; Saber S.

Journal: European Journal of Pharmaceutical Sciences

Publisher: Elsevier B.V.

Publication Date: July 2024

Volume / Issue: Volume 198

Article No.: 106792

ISSN: 9280987

DOI: 10.1016/j.ejps.2024.106792

Scopus: View on Scopus

PubMed: 38714237

Document Type: Article

Access: All Open Access; Gold Open Access

Authors and Affiliations

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; Youssef M.E., 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), Cairo, Badr City, 11829, Egypt, Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Cairo, Nasr City, 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, Shaqra, 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; Alharthi M.H., Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia; Alhalafi A.H., Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia; Bahashwan E., Department of Internal Medicine, Division of Dermatology, 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; BinAfif D.F., Department of Medicine, King Abdullah Medical City, Makkah, 24246, 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, Riyadh, 11597, Saudi Arabia; Elmorsy E.A., Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Saudi Arabia, Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt; AL-Noshokaty T.M., Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt; Fikry H., Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo, 11566, Egypt; Saleh L.A., Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, 11566, Egypt, Department of Pharmacology and Toxicology, Collage of Pharmacy, Taif University, Taif, 21944, Saudi Arabia; Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt

Abstract

Non-alcoholic steatohepatitis (NASH) is characterized by liver inflammation, fat accumulation, and collagen deposition. Due to the limited availability of effective treatments, there is a pressing need to develop innovative strategies. Given the complex nature of the disease, employing combination approaches is essential. Hedgehog signaling has been recognized as potentially promoting NASH, and cholesterol can influence this signaling by modifying the conformation of PTCH1 and SMO activity. HSP90 plays a role in the stability of SMO and GLI proteins. We revealed significant positive correlations between Hedgehog signaling proteins (Shh, SMO, GLI1, and GLI2) and both cholesterol and HSP90 levels. Herein, we investigated the novel combination of the cholesterol-lowering agent lovastatin and the HSP90 inhibitor PU-H71 in vitro and in vivo. The combination demonstrated a synergy score of 15.09 and an MSA score of 22.85, as estimated by the ZIP synergy model based on growth inhibition rates in HepG2 cells. In a NASH rat model induced by thioacetamide and a high-fat diet, this combination therapy extended survival, improved liver function and histology, and enhanced antioxidant defense. Additionally, the combination exhibited anti-inflammatory and anti-fibrotic potential by influencing the levels of TNF-α, TGF-β, TIMP-1, and PDGF-BB. This effect was evident in the suppression of the Col1a1 gene expression and the levels of hydroxyproline and α-SMA. These favorable outcomes may be attributed to the combination's potential to inhibit key Hedgehog signaling molecules. In conclusion, exploring the applicability of this combination contributes to a more comprehensive understanding and improved management of NASH and other fibrotic disorders. © 2024 The Author(s)

Keywords

Hedgehog signaling; HMG-CoA reductase inhibitors; HSP90 inhibitors; Lovastatin; Non-Alcoholic Steatohepatitis; PU-H71; Animals; Cholesterol; Diet, High-Fat; Drug Therapy, Combination; Hedgehog Proteins; Hep G2 Cells; HSP90 Heat-Shock Proteins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Male; Non-alcoholic Fatty Liver Disease; Rats; Rats, Sprague-Dawley; Signal Transduction; alanine aminotransferase; albumin; alkaline phosphatase; alpha smooth muscle actin; aspartate aminotransferase; collagen type I alpha 1 chain; gamma glutamyltransferase; glutathione; glutathione peroxidase; heat shock protein 90; hydroxymethylglutaryl coenzyme A reductase; hydroxyproline; malonaldehyde; messenger RNA; mevinolin; peroxidase; platelet derived growth factor BB; Smoothened protein; sonic hedgehog protein; thioacetamide; thiobarbituric acid reactive substance; tissue inhibitor of metalloproteinase 1; transcription factor Gli1; transforming growth factor beta; transforming growth factor beta1; triacylglycerol; tumor necrosis factor; zelavespib; zinc finger protein GLI2; hydroxymethylglutaryl coenzyme A reductase inhibitor; Shh protein, rat; adult; alanine aminotransferase blood level; albumin blood level; alkaline phosphatase blood level; animal experiment; animal model; animal tissue; antibody labeling; antiinflammatory activity; antioxidant activity; antiproliferative activity; Article; aspartate aminotransferase blood level; cholesterol blood level; collagen fiber; controlled study; drug potentiation; gamma glutamyl transferase blood level; gene expression; growth inhibition; Hep-G2 cell line; lipid diet; liver function; liver histology; nonalcoholic steatohepatitis; nonhuman; protein stability; rat; real time polymerase chain reaction; survival; synergistic effect; triacylglycerol blood level; adverse event; animal; combination drug therapy; drug effect; drug therapy; human; metabolism; nonalcoholic fatty liver; Sprague Dawley rat

Citation Information

Scopus Citations: 4

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