| Summary: | 博士 === 國立陽明大學 === 藥理學研究所 === 100 === Lung cancer is the leading cause of cancer death in Taiwan, United State, and the world. Approximately 85% of lung cancer patients belong to the non-small cell lung cancer (NSCLC). Lung adenocarcinoma 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, the activating mutations rate has been found in range from 10% to 15% in Caucasians and from 30% to 40% in Asians among the NSCLC patients. Thus, to develop the new agents or pinpoint novel approaches for improving the anti-tumor effects of gefitinib in patients with wild-type EGFR and acquired mutation in EGFR T790M have become an important and urgent mission. In the present study, by screening 598 herbal and natural compounds target on different EGFR status, we found curcumin could inhibit cell proliferation in different gefitinib-resistant NSCLC cell lines. Curcumin can improve the efficiency of gefitinib in the resistant NSCLC cells both in vitro and in vivo; 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. Furthermore, the combination treatment with curcumin and gefitinib synergistically inhibit cell proliferation in gefitinib-sensitive PC-9 and in H3255 cells might also through blocking EGFR activation by EGFR degradation. 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. The further study for curcumin analogues screening indicated that compound A showing not only the most potential activity for adenocarcinoma treatment, but also attenuate gefitinib-induced IEC-18 damage as well as curcumin. Taken together, these findings provide a novel treatment strategy that curcumin as an adjuvant to increase the spectrum of the usage of gefitinib in different EGFR status and overcome the gefitinib inefficiency in NSCLC patients.
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