title: The Janus kinases inhibitor AZD1480 attenuates growth of small cell lung cancers in vitro and in vivo.
abstract: OBJECTIVE
  The prognosis of small cell lung cancer (SCLC) is poor, and there has been very little progress in the medical treatment of SCLC in the past two decades. We investigated the potential of Janus-activated kinases (JAK) inhibitor, AZD1480, for treatment of SCLC in vitro and in vivo.
  
  
  METHODS
  JAK1 and JAK2 were inhibited by AZD1480 or siRNAs, and the effect of inhibition of JAK gene family on SCLC cell viability was evaluated. The effect of AZD1480 on cell-cycle distribution and apoptosis induction was studied. Antitumor effects of AZD1480 in tumor xenografts were assessed.
  
  
  RESULTS
  AZD1480 significantly inhibited growth of six out of 13 SCLC cells with IC50s ranging from 0.73 to 3.08 μmol/L. Knocking down of JAK2 and JAK1 inhibited proliferation of Jak2-positive/Jak1-negative H82 cells and Jak1-positive/Jak2-negative GLC4 cells, respectively. Treatment of SCLC cells with AZD1480 for 24 hours resulted in an increase of 4N DNA content and histone 3 serine 10 phosphorylation, indicative of G2-M phase arrest. Moreover, SCLCs underwent apoptosis after AZD1480 treatment as exemplified by the downregulation of MCL1, the accumulation of cleaved caspase 3, cleaved PARP, and increase of annexin-V-positive cells. Finally, xenograft experiments showed that AZD1480 attenuated the growth of H82 and GLC4 tumors in mice, and we observed stronger apoptosis as well as decreased CD31-positive endothelial cells in H82 and GLC4 xenografts upon AZD1480 treatment.
  
  
  CONCLUSIONS
  JAK inhibitor AZD1480 attenuated growth of SCLC cells in vitro and in vivo. Clinical development of anti-JAKs therapies in SCLC warrants further investigation.
authors.affiliation: Authors' Affiliations: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
authors.forename: Jih-Hsiang
authors.initials: JH
authors.lastname: Lee
authors.forename: Kang-Seo
authors.initials: KS
authors.lastname: Park
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Alberobello
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kallakury
authors.forename: Meng-Tzu
authors.initials: MT
authors.lastname: Weng
authors.forename: Yisong
authors.initials: Y
authors.lastname: Wang
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053613:Janus Kinase 1 / Q000096:biosynthesis / Q000235:genetics*; D053614:Janus Kinase 2 / Q000096:biosynthesis / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C545606:AZD 1480; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2