Celastrol Induces Apoptosis in Gefitinib-Resistant Non-Small Cell Lung Cancer Cells via Caspases-Dependent Pathways and Hsp90 Client Protein Degradation

Molecules

Xing-Xing Fan¹  Na Li¹  Jian-Lin Wu¹  Yan-Ling Zhou¹  Jian-Xing He²  Liang Liu¹ 

[1] State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau SAR, China;Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Disease, The 1st Affiliated Hospital of Guangzhou Medical College, Guangzhou 510120, China

关键词: celastrol;    gefitinib resistance;    NSCLC;    apoptosis;    Hsp90;    EGFR;   

DOI  :  10.3390/molecules19033508

来源: mdpi

【 摘 要 】

Celastrol, a triterpene extracted from the Chinese herb Tripterygium wilfordii, has been shown to have multiple bioactivities. Although among these activities, its anti-cancer effects have attracted the most attention, the effect of celastrol on gefitinib-resistant non-small cell lung cancer (NSCLC) cells is not clearly known. Here, we examined the potency of celastrol in three different NSCLC cell lines. We explored its treatment mechanism in two gefitinib-resistant NSCLC cell lines (H1650 and H1975). Our data demonstrated that celastrol exerted its apoptotic effect in a dose- and time-dependent manner. Also, the mitochondria membrane potential was gradually lost and the ratio of Bax/Bcl-2 increased after the treatment of celastrol, both of which are indicators of mitochondria membrane integrity. Although the caspases were activated, the treatment with pan-caspase inhibitor could partially inhibit the level of apoptosis. Moreover, the protein level of Hsp90 client proteins, EGFR and AKT, was measured. Interestingly, both client proteins were remarkably down-regulated after the treatment of celastrol. Taken together, our data showed that celastrol may be developed as a promising agent for treating gefitinib-resistant NSCLCs by inducing apoptosis through caspase-dependent pathways and Hsp90 client protein degradation.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.