title: AG490, a Jak2 inhibitor, suppressed the progression of murine ovarian cancer.
abstract: Ovarian cancer is the major cause of cancer death among female genital malignancies, and requires developing novel therapeutic measures. Immune escape and acquisition of tolerance by tumor cells are essential for cancer growth and progression. An immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) overexpression in tumors is essential for host immune tolerance. Janus-activated kinase-signal transducer and activator of transcription (JAK-STAT) pathway is involved in various kinds of tumor biology. Thus, we examined the effects of STAT1 inhibition by AG490 (a JAK2 inhibitor) on ovarian cancer progression in mice. In vitro study, IFN-γ treatment up-regulated Ido mRNA expression with STAT1 activation in OV2944-HM-1 cells, whereas AG490 treatment significantly inhibited this effect with the suppression of STAT1 phosphorylation. In vivo model, OV2944-HM-1 cells were intraperitoneally/subcutaneously transplanted into syngeneic immunocompetent female mice. AG490 treatment significantly suppressed subcutaneous tumor growth, compared with control. Consistently, in mice intraperitoneally inoculated HM-1 cells, the same treatment significantly improved survival rate with the reduced number of intraperitoneal tumors. Actually, intratumoral IDO expression was significantly suppressed with the reduction of STAT1 activation in AG490-treated mice. Moreover, in tumor microenvironment of mice treated with AG490, the accumulation of anti-tumor leukocytes such as CD8(+) T-cells, M1 macrophages, and NK cells was apparently exaggerated with the reciprocal reduction of regulatory T cells. Furthermore, intratumoral expression of anti-tumor cytokines such as IL-1α, IL-1β and IL-12 expression was significantly enhanced in mice treated with AG490. Collectively, JAK/STAT signal pathways may be good molecular target for immunotherapy of ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan; Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Kobayashi
authors.affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan; Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanizaki
authors.affiliation: Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kimura
authors.affiliation: Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Nosaka
authors.affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Toujima
authors.affiliation: Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kuninaka
authors.affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Minami
authors.affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Ino
authors.affiliation: Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan. Electronic address: kondot@wakayama-med.ac.jp.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kondo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors*; D020032:Tyrphostins / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2
keywords: Immune tolerance; Immunotherapy; JAK/STAT signal; Ovarian cancer; Peritoneal dissemination