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Effects and mechanisms of betulinic acid on improving EGFR TKI‐resistance of lung cancer cells
Author(s) -
Ko JiunnLiang,
Lin ChingHsiung,
Chen HengChung,
Hung WeiHeng,
Chien PengJu,
Chang HuiYi,
Wang BingYen
Publication year - 2018
Publication title -
environmental toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.813
H-Index - 77
eISSN - 1522-7278
pISSN - 1520-4081
DOI - 10.1002/tox.22621
Subject(s) - gefitinib , erlotinib , betulinic acid , lung cancer , epidermal growth factor receptor , cancer research , apoptosis , pharmacology , tyrosine kinase inhibitor , mtt assay , cancer , erlotinib hydrochloride , egfr inhibitors , medicine , chemistry , biology , oncology , biochemistry , genetics
Epidermal growth factor receptor (EGFR) mutations have been identified in approximately 55% of lung cancer patients in Taiwan. Gefitinib (Iressa) and Erlotinib (Tarceva) are the first‐generation targeting drugs to patients with EGFR gene mutants a work by inhibiting tyrosine kinase activity. However, resistance in EGFR‐mutated patients to first‐generation tyrosine kinase inhibitor (TKI) therapy after 8‐11 months of treatment has occurred. Betulinic acid (BetA) is a pentacyclic triterpenoid natural product derived from widespread plants. BetA has been reported to have a cytotoxic effect in several cancers. The purpose of this study is to investigate the effects and mechanisms of BetA on dampening EGFR TKI‐resistance of lung cancer cells. Our study has demonstrated by MTT assay that combining BetA and an EGFR TKI increased the cytotoxicity against EGFR TKI‐resistance lung cancer cells. Based on flow cytometry, combination treatments of BetA with an EGFR TKI enhanced Sub‐G1 accumulation, induced apoptosis and induced mitochondrial membrane potential loss. Using western blotting, BetA and EGFR TKI combined treatments inhibited cell cycle related protein and triggered apoptosis‐ and autophagy‐ related protein expression. Taken together, our data suggests that a target therapy combining BetA with an EGFR TKI improves drug efficacy in EGFR TKI‐resistant lung cancer cells.