4″-Alkyl EGCG Derivatives Induce Cytoprotective Autophagy Response by Inhibiting EGFR in Glioblastoma Cells

Satyam Singh; Priya Ghosh; Rajarshi Roy; Ananyaashree Behera; Revathy Sahadevan; Parimal Kar; Sushabhan Sadhukhan; Avinash Sonawane

doi:10.1021/acsomega.3c06110

4″-Alkyl EGCG Derivatives Induce Cytoprotective Autophagy Response by Inhibiting EGFR in Glioblastoma Cells

ACS Omega. 2024 Jan 3;9(2):2286-2301. doi: 10.1021/acsomega.3c06110. eCollection 2024 Jan 16.

Authors

Satyam Singh¹, Priya Ghosh¹, Rajarshi Roy¹, Ananyaashree Behera², Revathy Sahadevan³, Parimal Kar¹, Sushabhan Sadhukhan³, Avinash Sonawane¹

Affiliations

¹ Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh 453 552, India.
² School of Biotechnology, KIIT Deemed to be University, Bhubaneswar, Orissa 751 024, India.
³ Department of Chemistry, Indian Institute of Technology Palakkad, Palakkad, Kerala 678 623, India.

Abstract

Epidermal growth factor receptor (EGFR)-targeted therapy has been proven vital in the last two decades for the treatment of multiple cancer types, including nonsmall cell lung cancer, glioblastoma, breast cancer and head and neck squamous cell carcinoma. Unfortunately, the majority of approved EGFR inhibitors fall into the drug resistance category because of continuous mutations and acquired resistance. Recently, autophagy has surfaced as one of the emerging underlying mechanisms behind resistance to EGFR-tyrosine kinase inhibitors (TKIs). Previously, we developed a series of 4″-alkyl EGCG (4″-C_n EGCG, n = 6, 8, 10, 12, 14, 16, and 18) derivatives with enhanced anticancer effects and stability. Therefore, the current study hypothesized that 4″-alkyl EGCG might induce cytoprotective autophagy upon EGFR inhibition, and inhibition of autophagy may lead to improved cytotoxicity. In this study, we have observed growth inhibition and caspase-3-dependent apoptosis in 4″-alkyl EGCG derivative-treated glioblastoma cells (U87-MG). We also confirmed that 4″-alkyl EGCG could inhibit EGFR in the cells, as well as mutant L858R/T790M EGFR, through an in vitro kinase assay. Furthermore, we have found that EGFR inhibition with 4″-alkyl EGCG induces cytoprotective autophagic responses, accompanied by the blockage of the AKT/mTOR signaling pathway. In addition, cytotoxicity caused by 4″-C₁₀ EGCG, 4″-C₁₂ EGCG, and 4″-C₁₄ EGCG was significantly increased after the inhibition of autophagy by the pharmacological inhibitor chloroquine. These findings enhance our understanding of the autophagic response toward EGFR inhibitors in glioblastoma cells and suggest a potent combinatorial strategy to increase the therapeutic effectiveness of EGFR-TKIs.