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Updated: Jul 15, 2026
Ovarian Cancer Patient-Derived Organoid Models for Pre-Clinical Drug Testing
Published on: September 15, 2023
Repurposing natural compounds: computational evaluation of Piper longum alkaloids against ovarian cancer
Guruswamy Vimalkumar1, Abul Kalam Azad Mandal1
1School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
Background:
Ovarian cancer is a deadly gynaecological cancer, diagnosed at advanced stages, resistant to chemotherapy and with low survival rates. Current treatments are ineffective, and new multi-targeted candidates are needed. The alkaloids of Piper longum (piperine, piperlongumine, and piperlonguminine) have reported anti-cancer effects however, specific molecular targets and underlying mechanism of action in ovarian cancer remain largely unknown.
Methods:
DEGs from five GEO datasets were obtained using GEO2R (|log2FC| > 1, p < 0.05) and compared with alkaloid targets from SwissTargetPrediction, GeneCards, and CTD. Protein-protein interaction PPI networks were built with STRING v12.0, and hub genes were identified with CytoHubba and MCODE. Gene ontology, GEPIA2 expression, Kaplan-Meier survival, and GSCA mutation analyses confirmed clinical significance. Binding stability was evaluated using Molecular docking (AutoDock Vina) and molecular dynamics simulations (GROMACS, 2023.1, CHARMM36m 200 ns).
Results:
Cross-referencing 14,063 DEGs with 483 alkaloid targets yielded 342 shared genes. PPI analysis produced a robust network (292 nodes, 6,373 edges; p = 1.0 × 10-16), identifying ten hub genes: TP53, CTNNB1, AKT1, IL6, TNF, EGFR, CASP3, BCL2, MYC, and JUN. Of these, BCL2, EGFR, JUN, TNF, and TP53 were significantly dysregulated in tumour tissues, with JUN and EGFR as key adverse prognostic drivers. TP53 showed the highest mutation frequency (100%). Piperine exhibited the strongest docking affinity for EGFR (-8.701 kcal/mol), and MD simulations confirmed EGFR-piperine as the most stable complex (RMSD: 0.20-0.25 nm), driven by hydrophobic anchoring.
Conclusion:
P. longum alkaloids, especially piperine, display potent multi-targeted anti-ovarian cancer activity, with EGFR as the main validated binding site. They also have better pharmacokinetic profiles than paclitaxel. Our results offer a mechanistic rationale for phytochemical repurposing in ovarian cancer and a reproducible framework for future experimental validation.
Insights
Piper longum alkaloids, particularly piperine, show promise as multi-targeted treatments for ovarian cancer by inhibiting EGFR. These natural compounds offer a new therapeutic avenue with favorable pharmacokinetics compared to paclitaxel.
Area of Science:
- Oncology
- Pharmacology
- Bioinformatics
Background:
- Ovarian cancer is a deadly gynecological malignancy with poor prognosis due to late diagnosis and treatment resistance.
- Current therapies are insufficient, necessitating novel multi-targeted treatment strategies.
- Alkaloids from Piper longum exhibit anti-cancer properties, but their specific targets and mechanisms in ovarian cancer require elucidation.
Purpose of the Study:
- To identify molecular targets of Piper longum alkaloids in ovarian cancer.
- To investigate the anti-cancer mechanisms of these alkaloids.
- To evaluate the therapeutic potential of Piper longum alkaloids for ovarian cancer treatment.
Main Methods:
- Differential gene expression (DEG) analysis of five GEO datasets.
- Comparison of DEGs with alkaloid targets from SwissTargetPrediction, GeneCards, and CTD.
- Construction of protein-protein interaction (PPI) networks and identification of hub genes.
- Gene ontology, expression, survival, and mutation analyses.
- Molecular docking and molecular dynamics simulations to assess binding stability.
Main Results:
- 342 shared genes were identified between DEGs and alkaloid targets.
- A significant PPI network revealed ten hub genes, including TP53, CTNNB1, AKT1, IL6, TNF, EGFR, CASP3, BCL2, MYC, and JUN.
- EGFR and JUN were identified as key adverse prognostic drivers in ovarian tumors.
- TP53 exhibited 100% mutation frequency.
- Piperine demonstrated strong binding affinity to EGFR, confirmed by molecular dynamics simulations.
Conclusions:
- Piper longum alkaloids, especially piperine, exhibit multi-targeted anti-ovarian cancer activity, primarily through EGFR inhibition.
- These phytochemicals possess favorable pharmacokinetic profiles compared to paclitaxel.
- The study provides a mechanistic basis for repurposing Piper longum alkaloids and a framework for future validation.