Chemotherapeutic efficacy of dihydromyricetin ruthenium-p-cymene complex in lung cancer through modulation of the PI3K/β-catenin/AhR signaling cascade.

Flavonoids have been regarded as a potent bioactive chemical for the past few decades. When flavonoids complexed with metal ions, exceptional organometallic complexes with enhanced pharmacological and therapeutic qualities were formed. The novel dihydromyricetin ruthenium-p-cymene complex has been synthesized and characterized using the use of modern analytical methods like mass spectrometry, FTIR, UV-visible spectroscopy, scanning electron microscopy, and NMR spectroscopy. Molecular docking and pharmacokinetic studies have been carried out. The in vitro study has been executed through cell viability study, colony formation assay, apoptosis assay, cell cycle arrest study, and western blot study in A549 and NCI-H460 cells. The complex's toxicological profile has been evaluated using both acute and subacute toxicity study. The in vivo study has been performed through the administration of benzo[α]pyrene in mice, sustained for 6 months, and treated with different doses of the complex, followed by histopathology, immunohistochemistry, ki-67 expression level, and apoptosis assay by the TUNEL method have been performed. As a result, the compound has shown more potent antioxidant activity than free dihydromyricetin. Followed by the treatment with complex, the number and size of colonies have been reduced in association with the initiation of apoptosis. Downstream of AKT, β-catenin, and AhR expression was evaluated in a western blot study. From the toxicity study, doses of 50, 100, and 200 mg/kg were identified as safe for conducting in vivo chemotherapeutic studies of the novel complex. Treatment with the complex in mice demonstrated significant recovery of the normal cellular architecture in lung tissues. Immunohistochemical analysis revealed that decreased PI3K, m-TOR, β-catenin, and AhR expression, along with enhanced PTEN expression, correlated with the induction of apoptotic events. Thus, dihydromyricetin ruthenium-p-cymene complex has been proven as a strong chemotherapeutic drug by modifying PI3K/β-catenin/AhR signalling cascade inside lung cancer microenvironment, thereby causing apoptotic cell death.