Luteolin is effective in the non‐small cell lung cancer model withL858R/T790M EGFreceptor mutation and erlotinib resistance

• DOI: 10.1111/bph.12610
• Publication Date: 2014-01-29T08:48:37Z
• Authors: Zhuan Hong; Xiang Cao; Na Li; Yizhou Zhang; Lei Lan; Yi Zhou; Xiaolong Pan; Lei Shen; Zhimin Yin; Lan Luo
• Keywords: Male; 0301 basic medicine; Lung Neoplasms; Cell Survival; Mice, Nude; Antineoplastic Agents; Apoptosis; Adenocarcinoma; 3. Good health; ErbB Receptors; Erlotinib Hydrochloride; 03 medical and health sciences; Drug Resistance, Neoplasm; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Mutation; Quinazolines; Animals; Humans; HSP90 Heat-Shock Proteins; Luteolin; Protein Kinase Inhibitors

Background and PurposeNon‐small cell lung cancer (NSCLC) is one of the most commonly diagnosed malignancies in the world. Small‐molecule inhibitors of theEGF receptor'styrosine kinase domain (TKIs), including gefitinib and erlotinib, have been widely used for treatingNSCLC. 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‐resistantNSCLC, we evaluated the effects of luteolin, a naturally occurring flavanoid, onT790MmutantNSCLCcells.Experimental ApproachThe effect of luteolin on the viability ofNSCLCand normal cell lines was investigated using theCellCountingKit‐8 (CCK‐8) assay. Luteolin‐induced apoptosis was assessed by bivariateFITC‐annexinV/PIassay, andWestern blots were used to measured apoptotic proteins. Co‐immunoprecipitation was used to determine the effect of luteolin on the interaction betweenHsp90 and mutantEGFreceptors. The effect of luteolin on theAkt/mTORpathway was studied usingWestern blotting analysis. Its anti‐tumour efficacyin vivowas examined in a mouse xenograft model.Key ResultsLuteolin exerted significant anti‐tumourigenic effects on theEGFreceptorL858R/T790Mmutation and erlotinib‐resistantNSCLCboth at the cellular and animal levels. Mechanistically, luteolin induced degradation of the EGF receptor by inhibiting the association ofHsp90 with the mutantEGF receptor, and, therefore, preventedPI3K/Akt/mTORsignalling, which resulted inNSCLCcell apoptosis.Conclusion and ImplicationsLuteolin may be a potential candidate forNSCLCtherapy, especially for treatment of patients with acquired erlotinib‐resistantNSCLC.