title: Inhibition of the JAK/STAT pathway with ruxolitinib overcomes cisplatin resistance in non-small-cell lung cancer NSCLC.
abstract: This study was aimed to elucidate the roles of inhibition of related JAK/STAT pathways in regulating cytotoxicity induced by cisplatin in non-small-cell lung cancer (NSCLC) cell. We treated five non-small-cell lung cancer cell lines with cisplatin alone or with cisplatin and Jak2 inhibitor (ruxolitinib) and assessed cell viability, expression of Jak2 and STAT3 and cell apoptosis. We also investigated the effect of combination treatment inhibited tumor xenograft growth in two human NSCLC xenograft models bearing the cisplatin resistant (H1299) and sensitive (A549) cells. Different cell lines with different genetic background showed half-maximal inhibitory concentrations (IC50) of cisplatin from 4.66 to 68.28 µmol/L. They could be divided into cisplatin intrinsic resistant and cisplatin sensitive cell lines. In cisplatin-resistant cells with higher Jak2 and STAT3 expression, cisplatin and ruxolitinib combination dramatically suppressed the cell growth, down-regulated the expression of phosphorylated STAT3 and induced cleaved caspase-3 expression. Moreover combination with cisplatin and ruxolitinib also significantly inhibited the growth of resistant cell H1299, A549/DDP and H2347 in soft agar model. Finally, combination group significant inhibited the tumor growth and induced the caspase-3 expression compared with either single agent alone (P < 0.05) on the resistant cell xenografts model. The present study indicates that further study is warranted to determine the effectiveness of combination treatment with cisplatin and Jak2/stat3 pathway inhibitor for platinum-resistant NSCLC.
authors.affiliation: Department of Clinical Pharmacology, Pharmacy Care Center, Chinese PLA General Hospital, No.28 FuXing Road, Beijing, 100853, China, huyuan1980619@126.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.forename: Yin
authors.initials: Y
authors.lastname: Hong
authors.forename: YuanJie
authors.initials: Y
authors.lastname: Xu
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Dai-Hong
authors.initials: DH
authors.lastname: Guo
authors.forename: Yibang
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D064593:Heterografts; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008819:Mice, Nude; D009570:Nitriles; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C540383:ruxolitinib; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053148:Caspase 3; D002945:Cisplatin