Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells via IL-6/STAT3 Pathway Inhibition

• Published in: Biological & pharmaceutical bulletin 2017/08/01, Vol.40(8), pp.1306-1313
• Main Authors: Lou, Wei, Chen, Yan, Zhu, Ke-ying, Deng, Huizi, Wu, Tianhao, Wang, Jun
• Format: Article
• Language: English
• Subjects: acquired resistance; Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Diosgenin - analogs & derivatives; Diosgenin - pharmacology; Diosgenin - therapeutic use; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Epidermal growth factor; Epidermal growth factor receptors; Epithelial-Mesenchymal Transition - drug effects; epithelial–mesenchymal transition; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; erlotinib; Erlotinib Hydrochloride - pharmacology; Erlotinib Hydrochloride - therapeutic use; Humans; Interleukin 6; Interleukin-6 - metabolism; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Melanthiaceae - chemistry; Mesenchyme; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Non-small cell lung carcinoma; polyphyllin I; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase receptors; Resistance factors; Rhizome - chemistry; Rhizomes; Signal transduction; Signal Transduction - drug effects; Stat3 protein; STAT3 Transcription Factor - metabolism; Targeted cancer therapy; Transcription; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b17-00271

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the most important limiting factor for treatment efficiency in EGFR-mutant non-small cell lung cancer (NSCLC). Much work has linked the epithelial–mesenchymal transition (EMT) to the emergence of drug resistance, consequently, ongoing research has been focused on exploring the therapeutic options to reverse EMT for delaying or preventing drug resistance. Polyphyllin I (PPI) is a natural compound isolated from Paris polyphylla rhizomes and displayed anti-cancer properties. In the current work, we aimed to testify whether PPI could reverse EMT and overcome acquired EGFR-TKI resistance. We exposed HCC827 lung adenocarcinoma cells to erlotinib which resulted in acquired resistance with strong features of EMT. PPI effectively restored drug sensitivity of cells that obtained acquired resistance. PPI reversed EMT and decreased interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway activation in erlotinib-resistant cells. Moreover, addition of IL-6 partially abolished the sensitization response of PPI. Furthermore, co-treatment of erlotinib and PPI completed abrogation of tumor growth in xenografts, which was associated with EMT reversal. In conclusion, PPI serves as a novel solution to conquer the EGFR-TKI resistance of NSCLC via reversing EMT by modulating IL-6/STAT3 signaling pathway. Combined PPI and erlotinib treatment provides a promising future for lung cancer patients to strengthen drug response and prolong survival.