Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells

• Published in: Scientific reports Vol. 5; no. 1; p. 8477
• Main Authors: Cao, Wei, Liu, Ying, Zhang, Ran, Zhang, Bo, Wang, Teng, Zhu, Xianbing, Mei, Lin, Chen, Hongbo, Zhang, Hongling, Ming, Pinghong, Huang, Laiqiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-07-2015; Nature Publishing Group
• Subjects: 14/19; 631/154/349; 631/67/1612/1350; 64/60; 82/29; 82/51; 96/2; 96/95; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Antitumor activity; Apoptosis; Apoptosis - drug effects; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Survival - drug effects; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Enzyme-Linked Immunosorbent Assay; Epidermal growth factor receptors; Gefitinib; Glycoprotein gp130; Harringtonines - chemistry; Harringtonines - therapeutic use; Harringtonines - toxicity; Humanities and Social Sciences; Humans; Interleukin 6; Interleukin-6 - analysis; Interleukin-6 - metabolism; Janus kinase; Janus Kinase 1 - metabolism; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Mice; Mice, Nude; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; multidisciplinary; Non-small cell lung carcinoma; Phosphorylation; Phosphorylation - drug effects; Protein-tyrosine kinase; Quinazolines - toxicity; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Science; Signal Transduction - drug effects; Stat3 protein; STAT3 Transcription Factor - metabolism; Taxoids - therapeutic use; Taxoids - toxicity; Transplantation, Heterologous; Xenografts
• DOI: 10.1038/srep08477
• EISSN: 2045-2322

Tyrosine kinase inhibitors (TKIs) are mostly used in non-small cell lung cancer (NSCLC) treatment. Unfortunately, treatment with Gefitinib for a period of time will result in drug resistance and cause treatment failure in clinic. Therefore, exploring novel compounds to overcome this resistance is urgently required. Here we investigated the antitumor effect of homoharringtonine (HHT), a natural compound extracted from
Cephalotaxus harringtonia
, on Gefitinib-resistant NSCLC cell lines
in vitro
and
in viv
o. NCI-H1975 cells with EGFR T790M mutation are more sensitive to HHT treatment compared with that of A549 cells with wild type EGFR. HHT inhibited cells growth, cell viability and colony formation, as well as induced cell apoptosis through mitochondria pathway. Furthermore, we explored the mechanism of HHT inhibition on NSCLC cells. Higher level of interleukin-6 (IL-6) existed in lung cancer patients and mutant EGFR and TGFβ signal requires the upregulation of IL-6 through the gp130/JAK pathway to overactive STAT3, an oncogenic protein which has been considered as a potential target for cancer therapy. HHT reversiblely inhibited IL-6-induced STAT3 Tyrosine 705 phosphorylation and reduced anti-apoptotic proteins expression. Gefitinib-resistant NSCLC xenograft tests also confirmed the antitumor effect of HHT
in vivo
. Consequently, HHT has the potential in Gefitinib-resistant NSCLC treatment.