Curcumin induces EGFR degradation in lung adenocarcinoma and modulates p38 activation in intestine: the versatile adjuvant for gefitinib therapy.
Curcumin induces EGFR degradation in lung adenocarcinoma and modulates p38 activation in intestine: the versatile adjuvant for gefitinib therapy.
复制标题
DOI：
10.1371/journal.pone.0023756
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Yang PC
中科院分区：
文献类型：
--
作者：
Lee JY;Lee YM;Chang GC;Yu SL;Hsieh WY;Chen JJ;Chen HW;Yang PC
表皮生长因子受体（EGFR）L 858 R或外显子19缺失突变的非小细胞肺癌（NSCLC）患者对酪氨酸激酶抑制剂（TKI）吉非替尼有良好的反应。然而，携带野生型EGFR和EGFR T790 M获得性突变的患者对吉非替尼治疗耐药。在这里，我们表明姜黄素可以提高吉非替尼在体外和体内模型中耐药NSCLC细胞中的效率。在筛选了598种中药和天然化合物后，我们发现姜黄素可抑制不同吉非替尼耐药的NSCLC细胞株的细胞增殖;在携带野生型EGFR或T790 M EGFR的NSCLC细胞株中，姜黄素可通过促进EGFR降解，浓度依赖性地下调EGFR磷酸化。此外，姜黄素通过阻断EGFR活化和诱导吉非替尼耐药NSCLC细胞系凋亡增强吉非替尼的抗肿瘤活性;姜黄素和吉非替尼的联合治疗通过降低EGFR、c-MET、细胞周期蛋白D1的表达，并通过半胱天冬酶-8诱导细胞凋亡激活，9、PARP有趣的是，我们观察到联合治疗组与吉非替尼单药治疗相比，生存率更高，肠粘膜损伤更少。我们发现姜黄素通过改变肠上皮细胞p38丝裂原活化蛋白激酶（MAPK）的活化来减弱吉非替尼诱导的细胞增殖抑制和凋亡。姜黄素通过抑制细胞增殖、EGFR磷酸化、诱导EGFR泛素化和凋亡，增强吉非替尼在NSCLC细胞系和异种移植小鼠模型中的抗肿瘤活性。此外，姜黄素通过改变p38激活减弱吉非替尼诱导的胃肠道不良反应。这些发现提供了一种新的治疗策略，姜黄素作为佐剂，以增加吉非替尼的使用谱，克服吉非替尼在NSCLC患者中的无效性。
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. 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. 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.
登录
查看更多内容
影响因子：
11.2
作者：
Chen, Huei-Wen;Lee, Jen-Yi;Yang, Pan-Chyr
通讯作者：
Yang, Pan-Chyr
影响因子：
56.9
作者：
Engelman, Jeffrey A.;Zejnullahu, Kreshnik;Janne, Pasi A.
通讯作者：
Janne, Pasi A.
影响因子：
5.7
作者：
Kamat, Ashish M.;Sethi, Gautam;Aggarwal, Bharat B.
通讯作者：
Aggarwal, Bharat B.
影响因子：
3.6
作者：
Aggarwal, S;Ichikawa, H;Aggarwal, BB
通讯作者：
Aggarwal, BB
影响因子：
3.6
作者：
Chen, HW;Yu, SL;Yang, PC
通讯作者：
Yang, PC