Curcumin Induces EGFR Degradation in Lung Adenocarcinoma and Modulates p38 Activation in Intestine: The Versatile Adjuvant for Gefitinib Therapy

Abstract

BackgroundNon-small cell lung cancer (NSCLC) patients with L858R or exon 19 deletion mutations in epidermal growth factor receptor (EGFR) have good responses to the tyrosine kinase inhibitor (TKI), gefitinib. However, patients with wild-type EGFR and acquired mutation in EGFR T790M are resistant to gefitinib treatment. Here, we showed that curcumin can improve the efficiency of gefitinib in the resistant NSCLC cells both in vitro and in vivo models.Methods/Principal FindingsAfter screening 598 herbal and natural compounds, we found curcumin could inhibit cell proliferation in different gefitinib-resistant NSCLC cell lines; concentration-dependently down-regulate EGFR phosphorylation through promoting EGFR degradation in NSCLC cell lines with wild-type EGFR or T790M EGFR. In addition, the anti-tumor activity of gefitinib was potentiated via curcumin through blocking EGFR activation and inducing apoptosis in gefitinib-resistant NSCLC cell lines; also the combined treatment with curcumin and gefitinib exhibited significant inhibition in the CL1-5, A549 and H1975 xenografts tumor growth in SCID mice through reducing EGFR, c-MET, cyclin D1 expression, and inducing apoptosis activation through caspases-8, 9 and PARP. Interestingly, we observed that the combined treatment group represented better survival rate and less intestinal mucosal damage compare to gefitinib-alone therapy. We showed that curcumin attenuated the gefitinib-induced cell proliferation inhibition and apoptosis through altering p38 mitogen-activated protein kinase (MAPK) activation in intestinal epithelia cell.Conclusions/SignificanceCurcumin potentiates antitumor activity of gefitinib in cell lines and xenograft mice model of NSCLC through inhibition of proliferation, EGFR phosphorylation, and induction EGFR ubiquitination and apoptosis. In addition, curcumin attenuates gefitinib-induced gastrointestinal adverse effects via altering p38 activation. These findings provide a novel treatment strategy that curcumin as an adjuvant to increase the spectrum of the usage of gefitinib and overcome the gefitinib inefficiency in NSCLC patients.

Alternative drug therapies are superior to epidermal growth factor receptor -targeted chemotherapeutic drug responses in non-small cell lung cancer

“…However, the potential anti-tumour effect of curcumin combined with EGFR-TKIs on NSCLC has not yet been investigated. Lee et al (2011) recently found that curcumin has dual beneficial effects on gefitinib therapy in NSCLC (Lee et al, 2011). In that study, it was found that curcumin inhibited cell survival in lung adenocarcinoma cell lines, an effect that was associated with the down regulation of EGFR and inhibition of Erk1/2 activity for the first time.…”

“…This is the first report to show that curcumin can overcome the gefitinib inefficiency and inhibited EGFR protein kinase activity through down-regulating endogenous EGFR level via accelerating proteasome-ubiquitin activity and could significantly reduce not only pEGFR, but also EGFR protein expression in a concentration-dependent manner. Although previous studies have indicated that curcumin inhibited EGFR kinase activity and blocked ligand-induced EGFR activation in the different types of cells, these reports showed the amount of EGFR did not alter in the presence of curcumin (Lee et al, 2011). The roles of these natural products or secondary metabolites played in plants have only recently come to be appreciated in an analytical context.…”

“…There has been recent development in molecular targeted therapies, an available option in addition to conventional cancer treatments. Molecular-targeted therapeutic drugs can interfere with and block specific molecular pathways involved in cancer cell growth and progression (Chang et al, 2011). By screening the 598 herbal and natural compounds containing the range of alkaloids, sesquiterpenes, diterpenes, pentacyclic triterpenes, sterols and many other diverse representatives are now tested to the different gefitinib-resistant NSCLC cell lines, in vitro through cell proliferation assay.…”

“…Tobacco/cigarette smoke is the major cause of 80% lung cancer cases (Lee et al, 2011). However, lung cancer is far more common in never-smokers than smokers in some countries, especially within the Pacific Rim, particularly in females (Herbst et al, 2002).…”

Curcumin induces apoptosis of triple-negative breast cancer cells by inhibition of EGFR expression

“…Recent studies have shown that curcumin inhibits the EGFR, Her-2, Hh/Gli, Wnt/B-catenin and Notch signaling pathways (16,17). Curcumin has been reported to potentiate the antitumor activity of gefitinib in cell lines and a xenograft mice model of NSCLC through inhibition of proliferation, EGFR phosphorylation and induction of EGFR ubiquitination and apoptosis (18). Curcumin has also been shown to reduce EGFR mRNA transcription and protein expression, thus inhibiting the proliferation of bladder cancer cells (19).…”