STA-9090 in combination with a statin exerts enhanced protective effects in rats fed a high-fat diet and exposed to diethylnitrosamine and thioacetamide

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Abdelhamid A.M.; Saber S.; Hamad R.S.; Abdel-Reheim M.A.; Ellethy A.T.; Amer M.M.; Abdel-Hamed M.R.; Mohamed E.A.; Ahmed S.S.; Elsisi H.A.; Khodeir M.M.; Alkhamiss A.S.; AlSalloom A. A.; Abu Elgasim M.A.E.; Almansour Z.H.; Elesawy B.H.; Elmorsy E.A.

Journal: Frontiers in Pharmacology

Publisher: Frontiers Media SA

Publication Date: 4 September 2024

Volume / Issue: Volume 15

Article No.: 1454829

ISSN: 16639812

DOI: 10.3389/fphar.2024.1454829

Scopus: View on Scopus

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Abdelhamid A.M., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Hamad R.S., Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, Saudi Arabia, Central Laboratory, Theodor Bilharz Research Institute, Giza, Egypt; Abdel-Reheim M.A., Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, Saudi Arabia, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Egypt; Ellethy A.T., Department of Oral and Medical Basic Sciences, Biochemistry Division, College of Dentistry, Qassim University, Buraidah, Saudi Arabia; Amer M.M., Department of Anatomy, College of Medicine, Qassim University, Buraidah, Saudi Arabia, Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Abdel-Hamed M.R., Department of Anatomy, College of Medicine, Qassim University, Buraidah, Saudi Arabia, Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Mohamed E.A., Department of Anatomy, College of Medicine, Qassim University, Buraidah, Saudi Arabia, Department of Anatomy, Faculty of Medicine, Cairo University, Cairo, Egypt; Ahmed S.S., Department of Microbiology and Immunology, College of Medicine, Qassim University, Buraidah, Saudi Arabia; Elsisi H.A., Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah, Saudi Arabia, Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, Egypt; Khodeir M.M., Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia, Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt; Alkhamiss A.S., Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia; AlSalloom A. A., Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia; Abu Elgasim M.A.E., Department of Family and Community Medicine, College of Medicine, Qassim University, Buraidah, Saudi Arabia; Almansour Z.H., Biological Sciences Department, College of Science, King Faisal University, Hofuf, Saudi Arabia; Elesawy B.H., Department of Pathology, College of Medicine, Taif University, Taif, Saudi Arabia, Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Elmorsy E.A., Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraidah, Saudi Arabia

Abstract

Introduction: Liver fibrosis is a significant global health burden that lacks effective therapies. It can progress to cirrhosis and hepatocellular carcinoma (HCC). Aberrant hedgehog pathway activation is a key driver of fibrogenesis and cancer, making hedgehog inhibitors potential antifibrotic and anticancer agents. Methods: We evaluated simvastatin and STA-9090, alone and combined, in rats fed a high-fat diet (HFD) and exposed to diethylnitrosamine and thioacetamide (DENA/TAA). Simvastatin inhibits HMG-CoA reductase, depleting cellular cholesterol required for Sonic hedgehog (Shh) modification and signaling. STA-9090 directly inhibits HSP90 chaperone interactions essential for Shh function. We hypothesized combining these drugs may provide liver protective effects through complementary targeting of the hedgehog pathway. Endpoints assessed included liver function tests, oxidative stress markers, histopathology, extracellular matrix proteins, inflammatory cytokines, and hedgehog signaling components. Results: HFD and DENA/TAA caused aberrant hedgehog activation, contributing to fibrotic alterations with elevated liver enzymes, oxidative stress, dyslipidemia, inflammation, and collagen deposition. Monotherapies with simvastatin or STA-9090 improved these parameters, while the combination treatment provided further enhancements, including improved survival, near-normal liver histology, and compelling hedgehog pathway suppression. Discussion: Our findings demonstrate the enhanced protective potential of combined HMG CoA reductase and HSP90 inhibition in rats fed a HFD and exposed to DENA and TAA. This preclinical study could help translate hedgehog-targeted therapies to clinical evaluation for treating this major unmet need. Copyright © 2024 Abdelhamid, Saber, Hamad, Abdel-Reheim, Ellethy, Amer, Abdel-Hamed, Mohamed, Ahmed, Elsisi, Khodeir, Alkhamiss, A., Abu Elgasim, Almansour, Elesawy and Elmorsy.

Keywords

dyslipideamia; hedgehog pathway; HMG-CoA reductase; HSP90; inflammation/fibrosis; STA-9090; albumin; antifibrotic agent; antineoplastic agent; antioxidant; cholesterol; collagen type 1; cytokine; diethylnitrosamine; ganetespib; heat shock protein 70; heat shock protein 90; hydroxymethylglutaryl coenzyme A reductase; hydroxyproline; platelet derived growth factor BB; scleroprotein; simvastatin; Smoothened protein; sonic hedgehog protein; statin (protein); thioacetamide; tissue inhibitor of metalloproteinase 1; transcription factor Gli1; triacylglycerol; tumor necrosis factor; zinc finger protein GLI2; adult; animal cell; animal experiment; animal model; animal tissue; Article; body weight loss; cell infiltration; controlled study; decapitation; dyslipidemia; fibrogenesis; gene expression; hedgehog signaling; histopathology; immunohistochemistry; inflammation; lipid diet; liver cell carcinoma; liver fibrosis; liver function test; liver histology; liver injury; male; MTT assay; nonhuman; oxidative stress; rat; real time polymerase chain reaction; signal transduction

Citation Information

Scopus Citations: 7

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