Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Ruthenium biochanin-A complex ameliorates lung carcinoma through the downregulation of the TGF-β/PPARγ/PI3K/TNF-α pathway in association with caspase-3-mediated apoptosis

  • Ming Cao (Department of Thoracic Surgery, The First Hospital Affiliated with Shandong First Medical University) ;
  • Bo Fan (Department of Thoracic Surgery, The First Hospital Affiliated with Shandong First Medical University) ;
  • Tianchang Zhen (Department of Thoracic Surgery, The First Hospital Affiliated with Shandong First Medical University) ;
  • Abhijit Das (Department of Pharmacology, NSHM Knowledge Campus, Kolkata- Group of Institutions) ;
  • Junling Wang (Department of Respiratory and Critical Care, The First Hospital Affiliated with Shandong First Medical University)
  • Received : 2022.12.10
  • Accepted : 2023.03.23
  • Published : 2023.07.15
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Abstract

Lung cancer is the most often reported cancer with a terrible prognosis worldwide. Flavonoid metal complexes have exhibited potential chemotherapeutic effects with substantially low adverse effects. This study investigated the chemotherapeutic effect of the ruthenium biochanin-A complex on lung carcinoma in both in vitro and in vivo model systems. The synthesized organometallic complex was characterized via UV-visible spectroscopy, FTIR, mass spectrometry, and scanning electron microscopy. Moreover, the DNA binding activity of the complex was determined. The in vitro chemotherapeutic assessment was performed on the A549 cell line through MTT assay, flow cytometry, and western blot analysis. An in vivo toxicity study was performed to determine the chemotherapeutic dose of the complex, and subsequently, chemotherapeutic activity was assessed in benzo-α-pyrene-induced lung cancer mouse model by evaluating the histopathology, immunohistochemistry, and TUNEL assays. The IC50 value of the complex in A549 cells was found to be 20 µM. The complex demonstrated significant apoptosis induction, enhanced caspase-3 expression and cell cycle arrest with downregulated PI3K, PPARγ, TGF-β, and TNF-α expression in A549 cells. The in vivo study suggested that ruthenium biochanin-A therapy restored the morphological architecture of lung tissue in a benzo-α-pyrene-induced lung cancer model and inhibited the expression of Bcl2. Additionally, increased apoptotic events were identified with upregulation of caspase-3 and p53 expression. In conclusion, the ruthenium biochanin-A complex successfully amelioratedlung cancer incidence in both in vitro and in vivo models through the alteration of the TGF-β/PPARγ/PI3K/TNF-α axis with the induction of the p53/caspase-3-mediated apoptotic pathway.

Keywords

Acknowledgement

The authors are highly grateful to The First Hospital Affiliated with Shandong First Medical University for their continuous support and encouragement throughout the experiment.

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