Life sciences · 2024
Assessment of the therapeutic potential of a novel phosphoramidate acyclic nucleoside on induced hepatocellular carcinoma in rat model.
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Said Youssef A, Hammad Sherif F, Halim Mariam I, El-Moneim Ahmed Abd, Osman Ahmed
Аннотация
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.
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.