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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.
AuthorsAya Kobayashi, Yuko Tanizaki, Akihiko Kimura, Yuko Ishida, Mizuho Nosaka, Saori Toujima, Yumi Kuninaka, Sawako Minami, Kazuhiko Ino, Toshikazu Kondo
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 766 Pg. 63-75 (Nov 05 2015) ISSN: 1879-0712 [Electronic] Netherlands
PMID26410360 (Publication Type: Journal Article)
CopyrightCopyright © 2015 Elsevier B.V. All rights reserved.
Chemical References
  • Cytokines
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Jak2 protein, mouse
  • Janus Kinase 2
Topics
  • Animals
  • Cell Line, Tumor
  • Cytokines (metabolism)
  • Female
  • Indoleamine-Pyrrole 2,3,-Dioxygenase (genetics)
  • Janus Kinase 2 (antagonists & inhibitors)
  • Mice
  • Ovarian Neoplasms (drug therapy, metabolism)
  • STAT1 Transcription Factor (antagonists & inhibitors)
  • Tyrphostins (pharmacology, therapeutic use)

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