In silico identification and in vitro validation of alpha-hederin as a potent inhibitor of Wnt/β-catenin signaling pathway in breast cancer stem cells

Tolulope Peter Saliu; Nirwani Natasha Seneviratne; Mishal Faizan; Umapriyatharshini Rajagopalan; Damith Chathuranga Perera; Achyut Adhikari; Kanishka Sithira Senathilake; Prasanna Galhena; Kamani Hemamala Tennekoon; Sameera Ranganath Samarakoon

doi:10.1007/s40203-024-00199-z

In silico identification and in vitro validation of alpha-hederin as a potent inhibitor of Wnt/β-catenin signaling pathway in breast cancer stem cells

In Silico Pharmacol. 2024 Apr 12;12(1):31. doi: 10.1007/s40203-024-00199-z. eCollection 2024.

Affiliations

¹ Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka.
² Central Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, Nepal.

PMID: 38617708
PMCID: PMC11014832 (available on 2025-04-12)
DOI: 10.1007/s40203-024-00199-z

Abstract

Cancer stem cells (CSCs) play a vital role in metastasis, recurrence and chemoresistance in breast cancer. β-catenin, which is a frequently over activated protein in CSCs, binds to T-cell factor/lymphoid enhancer factor (Tcf/Lef) family transcription factors leading to ectopic expression of Wnt pathway responsive genes necessary for the maintenance and action of CSCs. With the aim of identifying a small molecules that can effectively eliminate CSCs, molecular docking studies were performed against the Tcf/Lef binding hotspot on β-catenin using a library of 100 natural or synthetic small molecules. Small molecule ligands giving docking energy better than - 7 kcal/mol were further investigated by binding interactions analysis and molecular dynamics (MD) simulations. These compounds were then investigated in vitro, for cytotoxicity against CSCs isolated from MDA-MB-231 triple negative breast cancer cells. Alpha-hederin (AH) was identified as the only compound in the selected library that has cytotoxicity against breast CSCs. AH was further investigated for it's ability to regulate Wnt pathway target genes (Cyclin D1 and CD44)and the tumor suppressor p53by real-time quantitative PCR. Absorption, distribution, metabolism, excretion and toxicity properties of the AH was predicted in silico. AH significantly down regulated the transcription of Cyclin D1 and CD44 while up-regulating the transcription of p53. AH was predicted to have acceptable drug likeness. Although AH is currently known to inhibit the growth of various cancer cells in vitro, present study demonstrated for the first time that it is a potent inhibitor of Wnt/β-catenin signaling pathway and induce apoptosis in breast CSCs.

Keywords: Anticancer; Beta catenin; Breast cancer; Cancer stem cells; Molecular docking; Wnt pathway.

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