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Integrative ethnopharmacological and mechanistic evaluation of Gnidia glauca alkaloids: Multi-target anticancer
Poorna Vivek Valleti1, Vadlapudi Kumar1, Poornima Vijendra Dittekoppa2
1Department of Studies in Biochemistry, Davangere University, Shivagangothri, Davangere, 577007, Karnataka, India.
Ethnopharmacological Relevance:
Gnidia glauca (Thymelaeaceae) is a medicinal plant documented in Indian traditional medicine for the treatment of inflammation, wounds, and tumor-like swelling. The scientific community, however, has not yet made a thorough research on the pharmacological mechanisms of its use.
Aim Of The Study:
To confirm the G. glauca traditional use represented by the alkaloid fraction (GgLAF) through an integrated pharmacological and computational study, especially focusing on the multi-target anticancer potential and mechanistic pathways.
Materials And Methods:
The cytotoxicity of GgLAF against MCF-7 cells was determined by the MTT assay at various concentrations, along with the positive controls (paclitaxel and camptothecin). The apoptotic phenomena were investigated by Annexin V/PI flow cytometry, DAPI staining, and caspase-3 activation. The polymerization of β-tubulin, topoisomerase I/II inhibition, and anti-angiogenic effects were, respectively, estimated by immunofluorescence, enzyme assays, and HUVEC tube formation. LC-MS and 1H NMR were used to isolate and identify the major alkaloids. ADMET profiling and molecular docking (AutoDock Vina) were performed against Bcl-2, Topo I/II, VEGFR-2, and β-tubulin.
Results:
GgLAF was able to demonstrate strong cytotoxicity (IC50 = 144.51 μg/mL) and to mediate caspase-dependent apoptosis (86.7 %). It caused the disintegration of the β-tubulin framework, was capable of inhibiting Topo I/II, and exhibited a remarkable anti-angiogenic effect. Docking study showed that harmidine and norcotinine had strong interactions with Topo II (-8.0 kcal/mol) and β-tubulin (-7.2 kcal/mol). ADMET information revealed that the compounds have good drug-like properties and a low toxicity profile.
Conclusions:
Findings from this study not only experimentally corroborate the ethnomedical use of G. glauca but also confers its alkaloids as multi-target anticancer lead compounds orchestrating their actions via apoptosis induction, mitotic arrest, DNA damage, and anti-angiogenesis. The integrative approach employed in this research acts as a bridge between ethnomedicinal wisdom and contemporary pharmacological validation, thus positioning G. glauca as a promising candidate for future oncotherapeutic drug discovery.
