title: ZSTK474, a specific phosphatidylinositol 3-kinase inhibitor, induces G1 arrest of the cell cycle in vivo.
abstract: 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.
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Okamura
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Mukai
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yoshimi
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Aki
authors.initials: A
authors.lastname: Hanyu
authors.forename: Asako
authors.initials: A
authors.lastname: Sakaue-Sawano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyawaki
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D014227:Triazines; C510150:ZSTK474