Abstract
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.
Highlights
Celastrol, a triterpene derived from the Chinese medical herb Trypterygium wilfordii [1], has been shown to be an effective treatment in multiple complex diseases, such as rheumatoid arthritis [2], lupus erythematosus [3], lateral sclerosis [4], Alzheimer’s disease [5] and asthma [6]
We examined the effect of celastrol on three non-small cell lung cancer (NSCLC) cell lines, H1650, H2228 and H1975
Both H1650 and H1975 harbor EGFR-activating mutations but are resistant to gefitinib [22], while H2228 harbors a wild-type EGFR that can be used as EGFR independent control cell line [26]
Summary
A triterpene derived from the Chinese medical herb Trypterygium wilfordii [1], has been shown to be an effective treatment in multiple complex diseases, such as rheumatoid arthritis [2], lupus erythematosus [3], lateral sclerosis [4], Alzheimer’s disease [5] and asthma [6]. It has been shown to have very powerful anti-cancer activity in many kinds of cancer cell types with various treatment mechanisms It inhibited the growth of tumor cells by suppressing angiogenesis in prostate cancer [7] and it inhibited IκBα kinase activation [8], proteasome activity [9], or vascular endothelial growth factor receptor (VEGFR) expression [10] to induce apoptosis. We have attempted to examine the levels of the apoptotic effect exerted by celastrol and study the anti-cancer mechanism of celastrol on the two gefitinib-resistant NSCLC cell lines, H1650 and H1975
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