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

Osama A Mohammed; Mahmoud E Youssef; Ahmed S Doghish; Rabab S Hamad; Mustafa Ahmed Abdel-Reheim; Mushabab Alghamdi; Mohannad Mohammad S Alamri; Jaber Alfaifi; Masoud I E Adam; Muffarah Hamid Alharthi; Abdullah Hassan Alhalafi; Emad Bahashwan; Assad Ali Rezigalla; Daad Fuad BinAfif; Sameh Abdel-Ghany; Mohammed A Attia; Elsayed A Elmorsy; Tohada M Al-Noshokaty; Heba Fikry; Lobna A Saleh; Sameh Saber

doi:10.1016/j.ejps.2024.106792

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

Eur J Pharm Sci. 2024 May 5:198:106792. doi: 10.1016/j.ejps.2024.106792. Online ahead of print.

Authors

Osama A Mohammed¹, Mahmoud E Youssef², Ahmed S Doghish³, Rabab S Hamad⁴, Mustafa Ahmed Abdel-Reheim⁵, Mushabab Alghamdi⁶, Mohannad Mohammad S Alamri⁷, Jaber Alfaifi⁸, Masoud I E Adam⁹, Muffarah Hamid Alharthi⁷, Abdullah Hassan Alhalafi⁷, Emad Bahashwan¹⁰, Assad Ali Rezigalla¹¹, Daad Fuad BinAfif¹², Sameh Abdel-Ghany¹³, Mohammed A Attia¹⁴, Elsayed A Elmorsy¹⁵, Tohada M Al-Noshokaty¹⁶, Heba Fikry¹⁷, Lobna A Saleh¹⁸, Sameh Saber²

Affiliations

¹ 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: oamohamed@ub.edu.sa.
² Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt.
³ 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_doghish@azhar.edu.eg.
⁴ 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.
⁵ 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. Electronic address: m.ahmed@su.edu.sa.
⁶ Department of Internal Medicine, Division of Rheumatology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
⁷ Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
⁸ Department of Child Health, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia.
⁹ Department of Medical Education and Internal Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
¹⁰ Department of Internal Medicine, Division of Dermatology, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia.
¹¹ Department of Anatomy, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
¹² Department of Medicine, King Abdullah Medical City, Makkah 24246, Saudi Arabia.
¹³ 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.
¹⁴ 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.
¹⁵ Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Saudi Arabia; Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt. Electronic address: a.almarsa@qu.edu.sa.
¹⁶ Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt.
¹⁷ Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
¹⁸ 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.

PMID: 38714237
DOI: 10.1016/j.ejps.2024.106792

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.

Keywords: HMG-CoA reductase inhibitors; HSP90 inhibitors; Hedgehog signaling; Lovastatin; Non-Alcoholic Steatohepatitis; PU-H71.