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Luteolin is effective in the non‐small cell lung cancer model with L 858 R / T 790 M EGF receptor mutation and erlotinib resistance
Author(s) -
Hong Zhuan,
Cao Xiang,
Li Na,
Zhang Yizhou,
Lan Lei,
Zhou Yi,
Pan Xiaolong,
Shen Lei,
Yin Zhimin,
Luo Lan
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12610
Subject(s) - luteolin , erlotinib , gefitinib , pharmacology , apoptosis , receptor , cancer research , tyrosine kinase , erlotinib hydrochloride , pi3k/akt/mtor pathway , biology , chemistry , microbiology and biotechnology , epidermal growth factor receptor , biochemistry , flavonoid , antioxidant
Background and Purpose Non‐small cell lung cancer ( NSCLC ) is one of the most commonly diagnosed malignancies in the world. Small‐molecule inhibitors of the EGF receptor's tyrosine kinase domain ( TKIs) , including gefitinib and erlotinib, have been widely used for treating NSCLC . Unfortunately, nearly all patients after initially experiencing a marked improvement while on these drugs, eventually progress to acquire resistance to TKIs. Because there is no effective therapeutic strategy to treat TKI‐resistant NSCLC , we evaluated the effects of luteolin, a naturally occurring flavanoid, on T 790 M mutant NSCLC cells. Experimental Approach The effect of luteolin on the viability of NSCLC and normal cell lines was investigated using the C ell C ounting K it‐8 ( CCK ‐8) assay. Luteolin‐induced apoptosis was assessed by bivariate FITC ‐annexin V/PI assay, and W estern blots were used to measured apoptotic proteins. Co‐immunoprecipitation was used to determine the effect of luteolin on the interaction between H sp90 and mutant EGF receptors. The effect of luteolin on the A kt/m TOR pathway was studied using W estern blotting analysis. Its anti‐tumour efficacy in vivo was examined in a mouse xenograft model. Key Results Luteolin exerted significant anti‐tumourigenic effects on the EGF receptor L 858 R / T 790 M mutation and erlotinib‐resistant NSCLC both at the cellular and animal levels. Mechanistically, luteolin induced degradation of the EGF receptor by inhibiting the association of H sp90 with the mutant EGF receptor , and, therefore, prevented PI3K/Akt/mTOR signalling, which resulted in NSCLC cell apoptosis. Conclusion and Implications Luteolin may be a potential candidate for NSCLC therapy, especially for treatment of patients with acquired erlotinib‐resistant NSCLC .