Synthesis, Characterization and Pharmacological Evaluation of Isoliquiritigenin Ruthenium-p-Cymene Organometallic Complex in MNNG-Induced Rat Gastric Cancer Chemotherapy: In Silico, In Vitro and In Vivo Methodologies

Abstract

Abstract

Gastric cancer remains the fifth most common cause of cancer-related deaths worldwide, underscoring the critical need for continued research to improve therapeutic outcomes. Coordination of flavonoids with metal ions results in the creation of distinctive organometallic complexes that often demonstrate improved stability and therapeutic efficacy. In the present study, a novel Isoliquiritigenin ruthenium-p-cymene complex was synthesized and optimized by utilizing various analytical techniques. The chemotherapeutic effects of complex were assessed in AGS and MKN-45 human gastric cancer cell lines through cytotoxicity, clonogenic, wound-healing, apoptosis, cell cycle, and western blot assays. In vivo safety was evaluated by acute and subacute toxicity studies, while pharmacokinetic profiling was performed through HPLC in rats. Chemotherapeutic efficacy was further investigated in MNNG-induced gastric cancer rat model over 24 weeks, followed by histopathological, immunohistochemical, qRT-PCR, Ki-67 proliferation, and TUNEL apoptosis analyses. The complex demonstrated dose-dependent cytotoxicity, reduced colony formation and cell migration, induced cell cycle arrest at S/G2 phases, and triggered apoptosis in cancer cells. Western blot analysis revealed significant modulation of β-catenin, FAK, PI3K, DNMT1, and p53 expression. Toxicological evaluation confirmed that doses of 5, 10, and 20 mg/kg were well tolerated. Pharmacokinetic analysis indicated moderate oral absorption (Tmax ≈ 3 h), AUC₀–₂₄ ≈ 25 ± 3.0 µg·h/mL, and half-life 16 ± 2.0 h. In vivo treatment demonstrated that the anticancer efficacy of the complex in MNNG-induced gastric cancer through downregulation of AKT, mTOR, β-catenin, c-Myc, GRB2, and Ki-67 expression while enhancing caspase-3-mediated apoptosis. These findings suggest that Isoliquiritigenin ruthenium-p-cymene complex exerts promising chemotherapeutic effects by modulating proliferative and apoptotic signaling pathways in gastric cancer.