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Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells.
- Source :
-
Scientific reports [Sci Rep] 2015 Jul 13; Vol. 5, pp. 8477. Date of Electronic Publication: 2015 Jul 13. - Publication Year :
- 2015
-
Abstract
- 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 vivo. 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.
- Subjects :
- Animals
Antineoplastic Agents chemistry
Antineoplastic Agents therapeutic use
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
Docetaxel
Drug Synergism
Enzyme-Linked Immunosorbent Assay
ErbB Receptors genetics
ErbB Receptors metabolism
Gefitinib
Harringtonines chemistry
Harringtonines therapeutic use
Homoharringtonine
Humans
Interleukin-6 analysis
Interleukin-6 metabolism
Janus Kinase 1 metabolism
Lung Neoplasms drug therapy
Lung Neoplasms metabolism
Lung Neoplasms pathology
Male
Mice
Mice, Nude
Mitochondria drug effects
Mitochondria metabolism
Phosphorylation drug effects
STAT3 Transcription Factor metabolism
Taxoids therapeutic use
Taxoids toxicity
Transplantation, Heterologous
Antineoplastic Agents toxicity
Apoptosis drug effects
Drug Resistance, Neoplasm drug effects
Harringtonines toxicity
Quinazolines toxicity
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 5
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 26166037
- Full Text :
- https://doi.org/10.1038/srep08477