Assessment of the therapeutic potential of a novel phosphoramidate acyclic nucleoside on induced hepatocellular carcinoma in rat model

作     者：Youssef A Said Sherif F Hammad Mariam I Halim Ahmed Abd El-Moneim Ahmed Osman 

作者机构：Biotechnology Program Basic and Applied Sciences Institute Egypt-Japan University of Science and Technology (E-JUST) 21934 New Borg El-Arab City Alexandria Egypt Biochemistry Department Faculty of Science Ain Shams University 11566 Cairo Egypt. Electronic address: youssef.farghali@ejust.edu.eg. Medicinal Chemistry Department PharmD Program Egypt-Japan University of Science and Technology (E-JUST) 21934 New Borg El-Arab City Alexandria Egypt Pharmaceutical Chemistry Department Faculty of Pharmacy Helwan University 11795 Cairo Egypt. Pathology Department Faculty of Medicine Ain Shams University 11566 Cairo Egypt. Graphene Center of Excellence Egypt-Japan University of Science and Technology (E-JUST) 21934 New Borg El-Arab City Alexandria Egypt Physical Chemistry Department National Research Centre (NRC) 12622 Cairo Egypt. Biochemistry Department Faculty of Science Ain Shams University 11566 Cairo Egypt. 

出 版 物：《Life sciences》 

年 卷 期：2024年

页      面：122669页

学科分类：0710[理学-生物学] 07[理学] 09[农学] 

主　　题：Diethylnitrosamine Hepatocellular carcinoma Phosphoramidate acyclic nucleoside Rat model Sorafenib 

摘      要：AIMS:Hepatocellular Carcinoma (HCC) is renowned as a deadly primary cancer of hepatic origin. Sorafenib is the drug-of-choice for targeted treatment of unresectable end-stage HCC. Unfortunately, great proportion of HCC patients showed intolerance or unresponsiveness to treatment. This study assesses potency of novel ProTide; SH-PAN-19 against N-Nitrosodiethylamine (DEN)-induced HCC in male Wistar rats, compared to Sorafenib. MAIN METHODS:Structural entity of the synthesized compound was substantiated via FT-IR, UV-Vis, H NMR and C NMR spectroscopic analysis. In vitro, SH-PAN-19 cytotoxicity was tested against 3 human cell lines; hepatocellular carcinoma; HepG-2, colorectal carcinoma; HCT-116 and normal fibroblasts; MRC-5. In vivo, therapeutic efficacy of SH-PAN-19 (300 mg/kg b.w./day) against HCC could be revealed and compared to that of Sorafenib (15 mg/kg b.w./day) by evaluating the morphometric, biochemical, histopathological, immunohistochemical and molecular key markers. KEY FINDINGS:SH-PAN-19 was relatively safe toward MRC-5 cells (IC = 307.6 μg/mL), highly cytotoxic to HepG-2 cells (IC = 24.9 μg/mL) and prominently hepato-selective (TSI = 12.35). Oral LD of SH-PAN-19 was 3000 mg/kg b.w. DEN-injected rats suffered hepatomegaly, oxidative stress, elevated liver enzymes, hypoalbuminemia, bilirubinemia and skyrocketed AFP plasma titre. SH-PAN-19 alleviated the DEN-induced alterations in apoptotic, angiogenic and inflammatory markers. SH-PAN-19 produced a 2.5-folds increase in Caspase-9 and downregulated VEGFR-2, IL-6, TNF-α, TGFβ-1, MMP-9 and CcnD-1 to levels comparable to that elicited by Sorafenib. SH-PAN-19 resulted in near-complete pathological response versus partial response achieved by Sorafenib. SIGNIFICANCE:This research illustrated that SH-PAN-19 is a promising chemotherapeutic agent capable of restoring cellular plasticity and could stop HCC progression.