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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

[ Vol. 17 , Issue. 4 ]

Author(s):

Ruzhen Zheng, Hao Jiang*, Jinhui Li, Xinge Liu and Hongwei XuPages 376-385 (10)

Abstract:


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.

Keywords:

PI3K, drug-resistance, gefitinib, NSCLC, polyphyllin, apoptosis.

Affiliation:

Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, Department of Oncology, Zhejiang Hospital, No.12 Lingyin Road, Hangzhou, Zhejiang 310013, Department of Chinese Medicine and Rehabilitation, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, Department of Oncology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, Department of Orthopaedics, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000

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