Attenuation of hTERT-dependent pathways by Hydrastis canadensis as a novel mechanism for inhibiting breast cancer cell proliferation

Abstract

Breast cancer (BCa) is marked by uncontrolled cell division, causing the reactivation of the multi-unit ribonucleoprotein telomerase enzyme by expression of the catalytic telomerase reverse transcriptase (hTERT) subunit. Targeting hTERT can therefore offer an advantage in BCa management. Medicinal plants such as Hydrastis canadensis, used in homeopathy has therefore been explored for BCa treatment. Hydrastis canadensis mother tincture (MT) showed the presence of phytoactive components exhibiting anti-cancerous potential. The components were identified by GC-MS analysis and 45 phytochemicals were then screened using in-silico tools. The protein targets of the active components were predicted by submitting the Simplified Molecular Input Line Entry System (SMILES) of the compounds to SwissTargetPrediction, giving active components targeting the hTERT protein. Molecular docking studies were performed on AutoDock 4.2 and Molecular Dynamics (MD) simulation studies on GROningen MAchine for Chemical Simulations (GROMACS) 2023.2. The MM/PBSA calculations were performed with the gmxMMPBSA package. The data was then validated through wet lab experiments, Linoleic acid and Gadoleic acid, as modulators of human telomerase reverse transcriptase (hTERT) were identified, influencing cancer cell survival. The results highlighted the mechanistic role of Hydrastis candensis to target the key oncogenic protein hTERT operative in breast cancer with potential therapeutic applications in cancer treatment.