EIF4A3 targeted therapeutic intervention in glioblastoma multiforme using phytochemicals from Indian medicinal plants – an integration of phytotherapy into precision onco-medicine

Abstract

Glioblastoma Multiforme (GBM), an aggressive brain tumor (grade-IV astrocytoma), poses treatment challenges. Poor prognosis results from the rapid growth, highlighting the role of EIF4A3 in regulating non-coding RNAs. EIF4A3 promotes the expression of several non-coding RNAs, viz, Circ matrix metallopeptidase 9 (MMP9), a prominent oncogene, by interacting with the upstream region of the circMMP9 mRNA transcript and acts on cell proliferation, migration, and invasion of GBM. However, research shows that EIF4A3 knockdown inhibits glioblastoma progression and increases apoptosis. In this study, we explored the efficiency of the phytochemicals from plants like Withania somnifera and Castanea sativa with potential anti-glioblastoma effects as obtained from the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) database. Consequently, we have performed a virtual screening of the compounds against the protein EIF4A3. We further investigated the efficiency of the shortlisted compounds based on docking scores evaluated using GOLD, AutoDock4.2, LeDock, and binding free energy analyses using Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA). Among the phytochemicals studied so far, several Withania-specific compounds from Withania somnifera and a single dietary compound, viz., Thiamine from Castanea sativa, have exhibited comparatively good blood-brain barrier permeability, significant binding affinity towards the EIF4A3, and good ADMET properties. Furthermore, we have verified the interaction stability of the lead molecules with EIF4A3 using MD simulations. Thus, the present study offers an opportunity to develop drug candidates targeting glioblastoma caused by EIF4A3 over-expression, integrating phytotherapy into precision oncology to create tailored and precise natural treatment strategies for cancer.

Communicated by Ramaswamy H. Sarma

Keywords:

• EIF4A3
• glioblastoma
• phytochemicals
• precision medicine
• virtual screening

Acknowledgments

J.B. expresses gratitude to the Department of Biotechnology, Maulana Abul Kalam Azad University of Technology, West Bengal, India. S.K. acknowledges the AICTE for providing her Doctoral Fellowship (Student ID: S2022283). D.D. sincerely thanks the Department of Biotechnology (Govt. of India) for the Postgraduate (M.Tech) studentship. IMK acknowledges the Department of Biotechnology, Government of India, for his Ph.D. fellowship (DBT/2019/IICB/1213). S.C. acknowledges CSIR-IICB for their support, both financially and infrastructurally.

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Funding

The author(s) reported there is no funding associated with the work featured in this article.