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<p>Drug resistance is one of the many intricate challenges in the treatment of cancer. Moreover, traditional treatments may induce significant adverse effects. Innovative formulations utilizing bioactive ingredients may mitigate these adverse effects. The objective of the current study was to assess the inhibitory effects of saponin and its nanoparticles on malate dehydrogenase (MDH) activity in silico, in vitro, and in vivo, as well as to clarify its anti-tumor effects in hepatocellular carcinoma (HCC). The molecular docking and MDH activity were detected. Moreover, liver and kidney functions tests were evaluated. MTT assay for sorafenib (reference drug), saponin, and its nano was examined to determine IC<sub>50</sub> on human hepatocellular cancer cell line (HepG2) and Normal Human Lung Fibroblast (NHLF) cells. In vivo studies include 11 groups of mice, which were divided into sorafenib, saponin, nano-saponin, and combination groups. The expression levels of MDH, Bax, Bcl-2, and p53 genes were evaluated. Histological investigation of liver tissue was assessed. The results revealed that sorafenib and saponin act as inhibitors of MDH with inhibitory constant (Ki) equal to 191.145 and 144.58 mM, respectively. The IC<sub>50</sub> of saponin and its nano was 38.96 and 27.79&#xa0;µg/mL, respectively. Also, the LD<sub>50</sub> of sorafenib, saponin, and its nano equal to 9.83, 20.745, and 17.91&#xa0;mg/kg body weight, respectively. In vivo studies indicated that saponin and nano-saponin exhibited anti-tumor effects by reducing MDH activity and enhancing histological liver architecture comparable to the control group combined with a significant reduction in Bcl-2 and MDH gene expression and a marked increase in Bax and p53 gene expressions. The most effective inhibition of MDH activity was found in those receiving treatment with both sorafenib and nano-saponin. Moreover, saponin and nano-saponin reduced the levels of oxidative stress parameters MDA and elevated glutathione peroxidase and catalase activities. Our findings elucidate that saponin and nano-saponin exhibit an anti-tumor effect on HCC via inhibiting the MDH enzyme, increasing sorafenib efficacy, and lowering oxidative stress levels.</p>

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The Role of Saponin and its Nanoparticles on Malate Dehydrogenase Activity against Liver Cancer

  • 期刊论文

  • 发表日期：

    2026年1月21日

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  • Doaa M. El Gamal,
  • Mohammed M. Gheit,
  • Eman F. Aboelfetoh,
  • Abeer A. Khamis,
  • Tarek M. Mohamed

摘要

Drug resistance is one of the many intricate challenges in the treatment of cancer. Moreover, traditional treatments may induce significant adverse effects. Innovative formulations utilizing bioactive ingredients may mitigate these adverse effects. The objective of the current study was to assess the inhibitory effects of saponin and its nanoparticles on malate dehydrogenase (MDH) activity in silico, in vitro, and in vivo, as well as to clarify its anti-tumor effects in hepatocellular carcinoma (HCC). The molecular docking and MDH activity were detected. Moreover, liver and kidney functions tests were evaluated. MTT assay for sorafenib (reference drug), saponin, and its nano was examined to determine IC50 on human hepatocellular cancer cell line (HepG2) and Normal Human Lung Fibroblast (NHLF) cells. In vivo studies include 11 groups of mice, which were divided into sorafenib, saponin, nano-saponin, and combination groups. The expression levels of MDH, Bax, Bcl-2, and p53 genes were evaluated. Histological investigation of liver tissue was assessed. The results revealed that sorafenib and saponin act as inhibitors of MDH with inhibitory constant (Ki) equal to 191.145 and 144.58 mM, respectively. The IC50 of saponin and its nano was 38.96 and 27.79 µg/mL, respectively. Also, the LD50 of sorafenib, saponin, and its nano equal to 9.83, 20.745, and 17.91 mg/kg body weight, respectively. In vivo studies indicated that saponin and nano-saponin exhibited anti-tumor effects by reducing MDH activity and enhancing histological liver architecture comparable to the control group combined with a significant reduction in Bcl-2 and MDH gene expression and a marked increase in Bax and p53 gene expressions. The most effective inhibition of MDH activity was found in those receiving treatment with both sorafenib and nano-saponin. Moreover, saponin and nano-saponin reduced the levels of oxidative stress parameters MDA and elevated glutathione peroxidase and catalase activities. Our findings elucidate that saponin and nano-saponin exhibit an anti-tumor effect on HCC via inhibiting the MDH enzyme, increasing sorafenib efficacy, and lowering oxidative stress levels.