RRC ID 38354
著者 Kobayashi A, Tanizaki Y, Kimura A, Ishida Y, Nosaka M, Toujima S, Kuninaka Y, Minami S, Ino K, Kondo T.
タイトル AG490, a Jak2 inhibitor, suppressed the progression of murine ovarian cancer.
ジャーナル Eur J Pharmacol
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.
巻・号 766
ページ 63-75
公開日 2015-11-5
DOI 10.1016/j.ejphar.2015.09.039
PII S0014-2999(15)30271-5
PMID 26410360
MeSH Animals Cell Line, Tumor Cytokines / metabolism Female Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics Janus Kinase 2 / antagonists & inhibitors* Mice Ovarian Neoplasms / drug therapy* Ovarian Neoplasms / metabolism STAT1 Transcription Factor / antagonists & inhibitors* Tyrphostins / pharmacology Tyrphostins / therapeutic use*
IF 3.263
引用数 16
WOS 分野 PHARMACOLOGY & PHARMACY
リソース情報
ヒト・動物細胞 OV2944-HM-1(RCB1483)