BACKGROUND:EGFR tyrosine kinase inhibitors (TKIs) are widely used for advanced nonsmall cell lung cancer (NSCLC) patients with a sensitizing EGFR mutation and provide a promising treatment strategy. However, acquired resistance to EGFR-TKIs restricts their application. The mechanisms underlying acquired resistance to TKIs have been explored and Phosphoinositide 3- kinase (PI3K)/Akt/mTOR pathway plays a very important role in NSCLC development as well as EGFR-TKI resistance. Polyphyllin II(PP II) is the main steroidal saponin constituent which derives from the root of Paris polychylia. OBJECTIVE:We examined the sensitizing effect of PP II to gefitinib on proliferation, apoptosis, PI3K/Akt/mTOR signaling pathway and tumor growth on gefitinib-resistant NSCLC in vitro and in vivo. METHODS:Gefitinib-resistant PC-9/ZD cells and gefitinib-sensitive PC-9 cells were used. In the absence of PI3K siRNA, MTT assay, Annexin V/PI analyses, Western blot, and Immunohistochemistry analysis by TUNEL assays for xenograft model were carried out. RESULTS:PP II promoted the anti-proliferative effects of gefitinib and gefitinib-induced apoptosis via activation of caspases and cleavage of PARP. PP II elevated sensitization of gefitinib through targeting the PI3K/Akt/mTOR. PP II with gefitinib treatment was more effective in inhibiting tumor growth and PI3K inactivation on gefitinib-resistant xenograft. CONCLUSION:The results indicated that PP II elevated sensitization of drug-resistant PC-9/ZD cells to gefitinib through the inhibition of PI3K/Akt/mTOR signaling pathway. It provides a potential new strategy to overcome gefitinib resistance for EGFR-TKI resistant NSCLC.

译文

背景:EGFR酪氨酸激酶抑制剂(TKIs)被广泛用于患有致敏性EGFR突变的晚期非小细胞肺癌(NSCLC)患者,并提供了有希望的治疗策略。但是,获得性对EGFR-TKI的耐药性限制了它们的应用。已经探究了获得的对TKIs耐药性的潜在机制,磷酸肌醇3-激酶(PI3K)/ Akt / mTOR途径在NSCLC的发展以及EGFR-TKI耐药性中起着非常重要的作用。 Polyphyllin II(PP II)是类固醇皂苷的主要成分,其来源于巴黎木瓜的根。
目的:我们研究了PP II对吉非替尼在体外和体内对吉非替尼耐药的NSCLC增殖,凋亡,PI3K / Akt / mTOR信号通路和肿瘤生长的敏化作用。
方法:使用耐吉非替尼的PC-9 / ZD细胞和对吉非替尼敏感的PC-9细胞。在没有PI3K siRNA的情况下,进行了MTT测定,膜联蛋白V / PI分析,蛋白质印迹和通过TUNEL测定的免疫组织化学分析,用于异种移植模型。
结果:PP II通过激活半胱氨酸蛋白酶和PARP的裂解,促进了吉非替尼的抗增殖作用和吉非替尼诱导的细胞凋亡。 PP II通过靶向PI3K / Akt / mTOR提高了吉非替尼的敏感性。吉非替尼治疗的PP II在耐吉非替尼的异种移植物中抑制肿瘤生长和PI3K失活更有效。
结论:PP II通过抑制PI3K / Akt / mTOR信号通路提高了耐药PC-9 / ZD细胞对吉非替尼的敏感性。它为克服吉非替尼对EGFR-TKI耐药的NSCLC的耐药性提供了潜在的新策略。

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