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Environ Toxicol. 2018 Nov;33(11):1153-1159. doi: 10.1002/tox.22621. Epub 2018 Aug 23.

Effects and mechanisms of betulinic acid on improving EGFR TKI-resistance of lung cancer cells.

Author information

1
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
2
Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
3
Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua City, Taiwan.
4
Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua City, Taiwan.
5
School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
6
School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
7
Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan.

Abstract

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.

KEYWORDS:

betulinic acid; lung cancer; tyrosine kinase inhibitor resistant

PMID:
30136359
DOI:
10.1002/tox.22621
[Indexed for MEDLINE]

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