Lupeol: Bioactivity-guided cytotoxic principle from Hymenocardia acida Tul. (Phyllantaceae) suppresses signaling pathways via polypharmacology antagonism

• Published in: South African journal of botany 2025-02, Vol.177, p.279-294
• Main Authors: Adedokun, Oluwasegun, Ayinde, Buniyamin, Maggi, Filippo, Barboni, Luciano
• Format: Article
• Language: English
• Subjects: Anticancer; ERK2; MAPK signaling pathway; Medicinal plants; Phytochemicals; Tyrosine kinase
• ISSN: 0254-6299
• DOI: 10.1016/j.sajb.2024.12.007

•Crude extract and aqueous fraction of Hymenocardia acida was scientifically established to possess cytotoxic potential using both benchtop and cancer cell lines models.•Bioactivity-guided isolation of cytotoxic principles from HA was carried out.•Lupeol was isolated and evaluated on some cancer cell lines.•Effect of lupeol on different receptors implicated in p13k/AKT/mTOR and Raf/MEK/ERK signaling pathways.•Key receptors with futuristic roles in drug development vis a vis lupeol and its derivatives were highlighted.•2D and 3D mechanistic inhibition was established against the promising receptors. The use of medicinal plants in the management of cancer and related ailments has been known since time immemorial among African people. Hymenocardia acida is one such plant. This research aimed at the determination of the cytotoxic bioactive principle(s) and mechanistic determination of its mechanism of action(s). Bench-top cytotoxicity screening was carried out using Saccharomyces cerevisiae (20 – 100 µg/mL) and Raniceps ranninus (20 – 400 µg/mL), while growth inhibitory assay was carried out using Sorghum bicolor (SB) (1 - 30 mg/mL) model, the bioactivity-guided isolation of cytotoxic principle(s) was carried out using a combination of different chromatographic techniques, and probable mechanism of action was determined using in silico model. The crude extract (HA) and aqueous fraction (HAQ) Hymenocardia acida exhibited 100 % mortality on the Raniceps ranninus (RR) at different concentrations (20 – 400 μg/mL), HA and HAQ produced a significant (p < 0.05) reduction in the radicle length of S. bicolor in a concentration-dependent manner throughout the period of the experiment. The concentration range of 7.81 and 250 µg/mL in HA and HAQ, produced 71.70 ± 1.12 – 98.99 ± 1.96 % cytotoxicity range against Saccharomyces cerevisiae. HA possesses a 28.90 % improvement in cytotoxic activity against HCT 116 colon cancer upon solvent partitioning, HA exhibited the highest activity against human H460 lung cancer (IC50 20.80 ± 6.10). The most active fraction of HA produced lupeol, which showed remarkable cytotoxic effects on the human HCT116 colon cancer cell lines at low concentrations. Lupeol had antagonist influence on human tyrosine kinase (cytotoxic) and ERK2 receptors (cytostatic; MAPK signaling). Findings from this research justified the ethnomedicinal claim of Hymenocardia acida in the treatment of tumour-related ailments