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

Youssef A Said; Sherif F Hammad; Mariam I Halim; Ahmed Abd El-Moneim; Ahmed Osman

doi:10.1016/j.lfs.2024.122669

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

Life Sci. 2024 Apr 25:122669. doi: 10.1016/j.lfs.2024.122669. Online ahead of print.

Authors

Youssef A Said¹, Sherif F Hammad², Mariam I Halim³, Ahmed Abd El-Moneim⁴, Ahmed Osman⁵

Affiliations

¹ 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.
² 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.
³ Pathology Department, Faculty of Medicine, Ain Shams University, 11566 Cairo, Egypt.
⁴ 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.
⁵ 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.

PMID: 38677390
DOI: 10.1016/j.lfs.2024.122669

Abstract

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, ¹H NMR and ¹³C 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 (IC₅₀ = 307.6 μg/mL), highly cytotoxic to HepG-2 cells (IC₅₀ = 24.9 μg/mL) and prominently hepato-selective (TSI = 12.35). Oral LD₅₀ 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.

Keywords: Diethylnitrosamine; Hepatocellular carcinoma; Phosphoramidate acyclic nucleoside; Rat model; Sorafenib.