摘要
背景:EGFR酪氨酸激酶抑制剂(TKIs)被广泛用于有致敏EGFR突变的晚期非小细胞肺癌(NSCLC)的患者,并提供有前景的治疗策略。然而,EGFR-TKIs获得性耐药限制了其应用。探索了基于酪氨酸激酶抑制剂(TKIs)获得性耐药的机制和磷脂酰肌醇3激酶(PI3K)/ Akt / mTOR信号通路在非小细胞肺癌的发展以及EGFR-TKI耐药中起着非常重要的作用。重楼皂苷II(PP II)是来源于Paris polychylia的根的主要的甾体皂苷成分。 目的:观察在体内外重楼皂苷II(PP II)对吉非替尼耐药的非小细胞肺癌细胞的增殖、凋亡、PI3K/Akt信号通路及肿瘤生长以及对吉非替尼的增敏作用。 方法:采用吉非替尼耐药细胞PC-9/ZD和吉非替尼敏感的PC-9细胞。没有PI3K siRNA,运用了MTT比色法,膜联蛋白V / PI分析,Western blot,通过 TUNEL检测异种移植模型的免疫组化分析。 结果:通过活化半胱天冬酶和裂解PARP,PP II促进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增强了对吉非替尼的致敏作用。PP II与吉非替尼的治疗更有效地抑制肿瘤生长和对吉非替尼耐药异种移植的PI3K的失活。 结论:结果表明,PPⅡ通过抑制PI3K/Akt/mTOR信号通路提高了耐药PC-9 / ZD细胞对吉非替尼的致敏作用。它提供了EGFR-TKI耐药的非小细胞肺癌克服对吉非替尼耐药的可能的新策略。
关键词: PI3K,耐药性,吉非替尼,非小细胞肺癌,重楼皂苷,细胞凋亡。
Current Cancer Drug Targets
Title:Polyphyllin II Restores Sensitization of the Resistance of PC-9/ZD Cells to Gefitinib by a Negative Regulation of the PI3K/Akt/mTOR Signaling Pathway
Volume: 17 Issue: 4
关键词: PI3K,耐药性,吉非替尼,非小细胞肺癌,重楼皂苷,细胞凋亡。
摘要: 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.Export Options
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Cite this article as:
Polyphyllin II Restores Sensitization of the Resistance of PC-9/ZD Cells to Gefitinib by a Negative Regulation of the PI3K/Akt/mTOR Signaling Pathway, Current Cancer Drug Targets 2017; 17 (4) . https://dx.doi.org/10.2174/1568009616666161213141608
DOI https://dx.doi.org/10.2174/1568009616666161213141608 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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