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
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.