title: Cell-cycle fate-monitoring distinguishes individual chemosensitive and chemoresistant cancer cells in drug-treated heterogeneous populations demonstrated by real-time FUCCI imaging.
abstract: Essentially every population of cancer cells within a tumor is heterogeneous, especially with regard to chemosensitivity and resistance. In the present study, we utilized the fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging system to investigate the correlation between cell-cycle behavior and apoptosis after treatment of cancer cells with chemotherapeutic drugs. HeLa cells expressing FUCCI were treated with doxorubicin (DOX) (5 μM) or cisplatinum (CDDP) (5 μM) for 3 h. Cell-cycle progression and apoptosis were monitored by time-lapse FUCCI imaging for 72 h. Time-lapse FUCCI imaging demonstrated that both DOX and CDDP could induce cell cycle arrest in S/G2/M in almost all the cells, but a subpopulation of the cells could escape the block and undergo mitosis. The subpopulation which went through mitosis subsequently underwent apoptosis, while the cells arrested in S/G2/M survived. The present results demonstrate that chemoresistant cells can be readily identified in a heterogeneous population of cancer cells by S/G2/M arrest, which can serve in future studies as a visible target for novel agents that kill cell-cycle-arrested cells.
authors.affiliation: a AntiCancer; Inc. ; San Diego , CA USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Miwa
authors.forename: Shuya
authors.initials: S
authors.lastname: Yano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kimura
authors.forename: Mako
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Toneri
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Fuminari
authors.initials: F
authors.lastname: Uehara
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hiroshima
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology*; D002945:Cisplatin; D004317:Doxorubicin; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D061848:Optical Imaging / Q000379:methods*; D016016:Proportional Hazards Models; D059008:Time-Lapse Imaging / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D002945:Cisplatin
keywords: FUCCI; GFP; HeLa; RFP; cancer; cell cycle; chemoresistance; chemosensitivity; cisplatinum; doxorubicin; time-lapse imaging; tumor heterogeneity