Canthaxanthin downregulates EGFR in NSCLC: network pharmacology, molecular docking, dynamics simulations, ADMET, and...

Area of Science:

• Pharmacology
• Computational Biology
• Oncology

Background:

• Non-small cell lung cancer (NSCLC) is a major cause of cancer mortality, with existing treatments facing limitations due to toxicity and drug resistance.
• Natural compounds, such as the carotenoid canthaxanthin, present a potential avenue for novel NSCLC therapies due to their demonstrated anticancer properties.

Purpose of the Study:

• To investigate the therapeutic potential of canthaxanthin against NSCLC using an integrated computational and experimental approach.
• To elucidate the molecular mechanisms underlying canthaxanthin's anti-NSCLC effects and assess its pharmacokinetic and safety profile.

Main Methods:

• Network pharmacology to identify shared targets between canthaxanthin and NSCLC.
• Molecular docking and dynamics simulations to evaluate binding affinities and complex stability.
• ADMET analysis for pharmacokinetic and toxicity prediction.
• In-vitro cytotoxicity assays (MTT) on NSCLC (A549) and normal lung (HEL 299) cells.

Main Results:

• Identified 34 shared targets, with EGFR, SRC, and CASP3 as key hubs, exhibiting strong binding affinities.
• Molecular dynamics simulations confirmed the stability of canthaxanthin-target complexes.
• ADMET analysis predicted favorable pharmacokinetics and low toxicity (Class 6).
• In-vitro assays demonstrated selective cytotoxicity of canthaxanthin against A549 cells (IC50 = 23.66 µg/mL) with a favorable selectivity index (2.64) compared to 5-fluorouracil (2.23).
• Pathway enrichment analysis indicated modulation of PI3K-AKT, MAPK signaling, and apoptosis pathways.

Conclusions:

• Canthaxanthin exhibits potent and selective anti-NSCLC activity through multi-target modulation, including inhibition of proliferation and migration, and induction of apoptosis.
• Computational predictions of stability and low toxicity were supported by experimental findings.
• Canthaxanthin's polypharmacological profile and favorable safety suggest its potential as an adjunct or alternative therapy for NSCLC, especially in cases of drug resistance.