Exploring the anticancer potential of double-active pharmaceutical ingredient, metforminium ibuprofenate: Integrating in vivo and in silico investigations

• Published in: Journal of molecular liquids Vol. 404; p. 124908
• Main Authors: Hussan, K.P. Safna, Layana, Joshy, Lekshmi, S., Thayyil, Mohamed Shahin, Babu, Thekkekara D.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.06.2024
• Subjects: Double-active pharmaceutical ingredient; In vivo and in silico studies; Solid tumour mouse model; Solid tumour mouse model; In vivo and in silico studies; Double-active pharmaceutical ingredient
• ISSN: 0167-7322; 1873-3166
• DOI: 10.1016/j.molliq.2024.124908

•Showcasing the anticancer potential of a novel Dual-Active Pharmaceutical Ingredient (d-API) metforminium ibuprofenate (MtHIb).•Comprehensive In Vivo and insilico Assessment provides a robust foundation for further exploration, supporting the compound's potential anti-tumour efficacy.•Demonstrated MtHIb's inhibitory effects on tumor growth utilizing a solid-tumor mouse model.•Provide valuable molecular-level insights into MtHIb's biological impact through multifaceted approach at a cellular level.•Advanced molecular docking analyses explore MtHIb's interactions with diverse cancer-related protein targets. Rationale: A novel double active pharmaceutical ingredient (d-API), metforminium ibuprofenate (MtHIb) was synthesised by combining metformin hydrochloride (MtHCl) and sodium ibuprofen (NaIb). This formulation exhibits anti-diabetic and anti-inflammatory properties similar to its parent compounds, along with a remarkable antiproliferative effect on diverse cancer cells. The present study is aimed to analyse the anticancer potential of MtHIb by mouse tumour model and molecular docking. Solid tumour was induced by Dalton's Lymphoma Ascites (DLA) cells in Swiss albino mice, and d-API was administered orally. The tumour volume was measured using Vernier calliper and the activity of γ-glutamyl transferase (GGT) was assessed. The potential interactions of MtHIb with target proteins mTOR, HER2, EGFR, CDK4, CDK6, ERα/β, progesterone, COX2, BUB1, and KEAP2 were analyzed in silico. A significant reduction in tumour size was observed in mice treated with MtHIb. On the 30th day, the tumour volume, which was 8.12 cm3 in untreated animals, decreased to 1.311 cm3 with the treatment of 5 mg/kg b.wt of MtHIb, representing an 83.8 % reduction. The activity of GGT, a marker enzyme of proliferative activity, was considerably reduced from 394.87 to 51.26 U/mg protein/L. Molecular docking studies indicated that MtHIb exhibited strong binding affinity towards all the screened target proteins, specifically HER2, EGFR, CDK4, and BUB1. The findings suggest that MtHIb has promising anti-tumour effect, as evidenced by its significant reduction in tumour size and GGT activity in mice. The strong binding affinity of MtHIb towards the key cancer related proteins further supports its potential as a therapeutic agent against cancer, particularly in targeting pathways involved in cell proliferation and survival. Further preclinical and clinical studies are required to validate these findings and to explore the full therapeutic potential of MtHIb in cancer treatment.