期刊
EUROPEAN JOURNAL OF CANCER
卷 48, 期 6, 页码 936-943出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2011.10.006
关键词
Phosphatidylinositol 3-kinase (PI3K) inhibitor; ZSTK474; G1 arrest of the cell cycle; Antitumour agents; In vivo imaging
类别
资金
- Zenyaku Kogyo Co., Ltd.
- Japan Society for the Promotion of Science [22240092, 22700929]
- Ministry of Education, Culture, Sports, Science and Technology of Japan [221S0001]
- Grants-in-Aid for Scientific Research [22240092, 22700929, 22700890] Funding Source: KAKEN
Phosphatidylinositol 3-kinase (PI3K) is regarded as a promising therapeutic target because it is often activated in cancer. We previously reported that ZSTK474, a specific PI3K inhibitor, inhibits tumour cell proliferation via G1 arrest of the cell cycle without inducing apoptosis in vitro. However, it remained unclear whether ZSTK474 induces G1 arrest to exert antitumour efficacy in vivo. We recently developed a live imaging system, named Fluorescent Ubiquitination-based Cell Cycle Indicator (Fucci), to visualise cell cycle distribution. Here, by using this system, we tested whether ZSTK474 induces G1 arrest in tumour cells in vivo, as well as in vitro. Fucci-introduced human breast cancer MCF-7 cells and cervical cancer HeLa cells were subcutaneously xenografted in nude mice. ZSTK474 was administered to the tumour-bearing mice for 5 days, and the cell cycle distribution in the xenografted tumours were analysed by monitoring fluorescence in live mice. We demonstrate that ZSTK474 induces G1arrest along with tumour suppression in vivo. Moreover, we show that ZSTK474 suppresses the tumour growth without inducing apoptosis. Interestingly, such increase in G1 cells and tumour suppression was maintained during long-term (3-month) administration of ZSTK474. These results suggest that ZSTK474 exerts its in vivo antitumour efficacy via G1 arrest but not via apoptosis as long as it is administered, and could be used for months as maintenance therapy for patients with advanced cancers. (C) 2011 Elsevier Ltd. All rights reserved.
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