Deciphering the Anticancer Arsenal of Piper longum: Network Pharmacology and Molecular Docking Unveil Phytochemical Targets Against Lung Cancer

Abstract

Introduction: Lung cancer, characterized by uncontrolled cellular proliferation within the lung tissues, is the predominant cause of cancer-related fatalities worldwide. The traditional medicinal herb Piper longum has emerged as a significant contender in oncological research because of its documented anticancer attributes, suggesting its potential for novel therapeutic development. Methods: This study adopted network pharmacology and omics methodology to elucidate the anti-lung cancer potential of P. longum by identifying its bioactive constituents and their corresponding molecular targets. Results: Through a comprehensive literature review and the Integrated Medicinal Plant Phytochemistry and Therapeutics database (IMPPAT), we identified 33 bioactive molecules from P. longum. Subsequent analyses employing tools such as SwissTargetPrediction, SuperPred, and DIGEP-Pred facilitated the isolation of 676 potential targets, among which 72 intersected with 666 lung cancer-associated genetic markers identified through databases including the Therapeutic Target Database (TTD), Online Mendelian Inheritance in Man (OMIM), and GeneCards. Further validation through protein-protein interaction (PPI) networks, gene ontology, pathway analyses, boxplots, and overall survival metrics underscored the therapeutic potential of compounds such as 7-epi-eudesm-4(15)-ene-1β, demethoxypiplartine, methyl 3,4,5-trimethoxycinnamate, 6-alpha-diol, and aristolodione. Notably, our findings reaffirm the relevance of lung cancer genes, such as CTNNB1, STAT3, HIF1A, HSP90AA1, and ERBB2, integral to various cellular processes and pivotal in cancer genesis and advancement. Molecular docking assessments revealed pronounced affinity between 6-alpha-diol and HIF1A, underscoring their potential as therapeutic agents for lung cancer. Conclusion: This study not only highlights the bioactive compounds of P. longum but also reinforces the molecular underpinnings of its anticancer mechanism, paving the way for future lung cancer therapeutics.

Keywords: Bioactivity; Computational screening; Drug discovery; Medicinal plant compounds; Oncogenes.

Figure 1

Predicted BOILED-Egg diagram of the selected compounds. BBB - Blood Brain Barrier, HIA - Human Intestinal Absorption, PGP⁺ - substrate of P-glycoprotein and PGP^- - non-substrate of P-glycoprotein

Figure 2

Intersecting targets between the active phytochemical potential protein targets in P. longum and Lung cancer-related genes.

Figure 3

(a) The PPI network of the 72 intersecting targets and (b) The PPI network of the top 20 target genes were constructed.

Figure 4

Compound - Target - Disease network of P. longum and lung cancer.

Figure 5

Top 20 GO terms and KEGG pathways associated with P. longum and lung cancer. a) Molecular Functions, b) Cellular Components c) Biological Processes and d) KEGG pathway.

Figure 6

Box plots encode the 5-lung cancer associated gene expression levels [a)CTNNB1, b) ERBB2, c) HIF1A, d) HSP90AA1, e) STAT3] in LUAD and LUSC compared with normal cells. Tumor tissues are marked in cyan color and noncancerous or normal tissues are marked in grey color.

Figure 7

The survival heat map represents the prognostic impacts of unique gene expression levels based on the TCGA_LUAD and TCGA_LUSC datasets. The heat map represents the hazard ratios in log10 scale for the lung cancer associated genes. Red color represents higher risks, blue color indicates lower risks. The darkened rectangular frames indicate the significant favorable and unfavorable results in prognostic analyses.

Figure 8

Lung cancer associated unique genes and their prognostic value is represented by overall survival analyses (Kaplan - Meier plotters and logrank tests) based on TCGA_LUAD and _LUSC visualized by GEPIA2. The dashed lines denote upper and lower confidence intervals. a) CTNNB1, b) ERBB2, c) HIF1A, d) HSP90AA1, e) STAT3.

Figure 9

Molecular docking results of key Bioactive of P.longum with lung cancer core targets (a) CTNNB1 docked with Aristolodione (b) HIF1A docked with Aristolodione (c) STAT3 docked with 6-alpha-diol (d) STAT3 docked with Aristolodione (e) HIF1A docked with 6-alpha-diol.