Unlocking the anticancer role of alpha-phellandrene via TRPM4 channel modulation in lung cancer

Abstract

Lung cancer remains one of the leading causes of death worldwide, and in major cases accounts for non-small cell lung cancer (NSCLC). Recent advances in targeted therapy have greatly improved treatment outcomes by concentrating on specific genes, proteins, and signaling pathways in tumors, providing a precise treatment method that causes less damage to healthy cells. In the context of targeted therapy, one more target biomarker has been identified, ion channels, which have been considered diverse regulators in the progression of lung cancer. Transient receptor potential (TRP) channels have captivated tremendous appreciation as promising drug targets over the past few years. Importantly, TRPM, a family of TRP that are key regulators of calcium homeostasis, have emerged as promising therapeutic targets due to their overexpression in various cancers, including lung cancer, as well as their involvement in tumor progression, metastasis, and apoptosis resistance. This study investigates the potential of naturally occurring monoterpenes as TRPM channel modulators using an in silico approach. Fifteen monoterpenes were selected and evaluated for their pharmacokinetic properties (ADMET), drug-likeness, and molecular docking study against TRPM2, TRPM4, TRPM5, TRPM7, and TRPM8 isoforms. Alpha-Phellandrene showed significant binding affinity toward TRPM4 (-6.0 kcal/mol) and notably shared key binding residues (ARG960, TYR964, GLU978, GLN976, PRO975, GLN973, LEU968) with the standard inhibitor 9-Phenanthrol, indicating its potential as a natural mimic. Molecular dynamics (MD) simulations further validated the structural stability of the TRPM4–alpha–phellandrene complex over 100 ns. Research findings suggested alpha-phellandrene as a promising candidate for developing TRPM4-targeted therapies in lung cancer.