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Curcumin induces EGFR degradation in lung adenocarcinoma and modulates p38 activation in intestine: the versatile adjuvant for gefitinib therapy.
PLoS One 2011; 6(8):e23756Plos

Abstract

BACKGROUND

Non-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 FINDINGS

After 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/SIGNIFICANCE

Curcumin 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.

Authors+Show Affiliations

Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21858220

Citation

Lee, Jen-Yi, et al. "Curcumin Induces EGFR Degradation in Lung Adenocarcinoma and Modulates P38 Activation in Intestine: the Versatile Adjuvant for Gefitinib Therapy." PloS One, vol. 6, no. 8, 2011, pp. e23756.
Lee JY, Lee YM, Chang GC, et al. Curcumin induces EGFR degradation in lung adenocarcinoma and modulates p38 activation in intestine: the versatile adjuvant for gefitinib therapy. PLoS ONE. 2011;6(8):e23756.
Lee, J. Y., Lee, Y. M., Chang, G. C., Yu, S. L., Hsieh, W. Y., Chen, J. J., ... Yang, P. C. (2011). Curcumin induces EGFR degradation in lung adenocarcinoma and modulates p38 activation in intestine: the versatile adjuvant for gefitinib therapy. PloS One, 6(8), pp. e23756. doi:10.1371/journal.pone.0023756.
Lee JY, et al. Curcumin Induces EGFR Degradation in Lung Adenocarcinoma and Modulates P38 Activation in Intestine: the Versatile Adjuvant for Gefitinib Therapy. PLoS ONE. 2011;6(8):e23756. PubMed PMID: 21858220.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Curcumin induces EGFR degradation in lung adenocarcinoma and modulates p38 activation in intestine: the versatile adjuvant for gefitinib therapy. AU - Lee,Jen-Yi, AU - Lee,Yee-Ming, AU - Chang,Gee-Chen, AU - Yu,Sung-Liang, AU - Hsieh,Wan-Yu, AU - Chen,Jeremy J W, AU - Chen,Huei-Wen, AU - Yang,Pan-Chyr, Y1 - 2011/08/17/ PY - 2011/05/27/received PY - 2011/07/24/accepted PY - 2011/8/23/entrez PY - 2011/8/23/pubmed PY - 2012/2/16/medline SP - e23756 EP - e23756 JF - PloS one JO - PLoS ONE VL - 6 IS - 8 N2 - BACKGROUND: Non-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 FINDINGS: After 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/SIGNIFICANCE: Curcumin 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/21858220/Curcumin_induces_EGFR_degradation_in_lung_adenocarcinoma_and_modulates_p38_activation_in_intestine:_the_versatile_adjuvant_for_gefitinib_therapy_ L2 - http://dx.plos.org/10.1371/journal.pone.0023756 DB - PRIME DP - Unbound Medicine ER -