JAK2 inhibitor TG101348 overcomes erlotinib-resistance in non-small cell lung carcinoma cells with mutated EGF receptor
| Autor: | Shanzhou Duan, Ying-chen Xia, Wentao Yang, Yongbing Chen, Fuquan Zhang, Rongying Zhu |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Pathology
medicine.medical_specialty erlotinib Lung Neoplasms Pyrrolidines TG101348 Mice Nude Apoptosis Erlotinib Hydrochloride Mice Carcinoma Non-Small-Cell Lung Survivin Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans heterocyclic compounds Epidermal growth factor receptor neoplasms non-small cell lung cancer Cell Proliferation Sulfonamides TUNEL assay drug resistance biology business.industry Cell growth Drug Synergism Janus Kinase 2 JAK2 Inhibitor TG101348 Xenograft Model Antitumor Assays respiratory tract diseases ErbB Receptors Oncology Terminal deoxynucleotidyl transferase Drug Resistance Neoplasm Cancer research biology.protein cancer therapy Female Erlotinib business medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, NSCLC patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of TG101348 (a JAK2 inhibitor) on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation, apoptosis, gene expression and tumor growth were evaluated by diphenyltetrazolium bromide (MTT) assay, flow cytometry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, Western Blot and a xenograft mouse model, respectively. Results showed that erlotinib had a stronger impact on the induction of apoptosis in erlotinib-sensitive PC-9 cells but had a weaker effect on erlotinib-resistant H1975 and H1650 cells than TG101348. TG101348 significantly enhanced the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, stimulated erlotinib-induced apoptosis and downregulated the expressions of EGFR, p-EGFR, p-STAT3, Bcl-xL and survivin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of TG101348 and erlotinib induced apoptosis, inhibited the activation of p-EGFR and p-STAT3, and inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that TG101348 is a potential adjuvant for NSCLC patients during erlotinib treatment. |
| Databáze: | OpenAIRE |
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