title: Dynamic color-coded fluorescence imaging of the cell-cycle phase, mitosis, and apoptosis demonstrates how caffeine modulates cisplatinum efficacy.
abstract: Caffeine enhances the effect of certain anticancer drugs, but the mechanism of modulation is poorly understood. In this study, modulation of cisplatinum efficacy induced by caffeine was visualized at the subcellular level by real-time fluorescent-protein imaging. Mitotic and apoptotic changes were observed by imaging 143B human osteosarcoma dual-color cells, in which GFP is expressed in the nucleus and RFP is expressed in the cytoplasm. Modulation of the cell cycle was imaged using time-lapse imaging of HeLa cells expressing a fluorescent ubiquitination-based cell cycle indicator (FUCCI) in the nucleus. Clonogenic assays showed that caffeine increased the inhibition by cisplatinum on cell proliferation. Subcellular imaging demonstrated that cisplatinum decreased mitosis and induced apoptosis in 143B cells. The combination of cisplatinum and caffeine enhanced mitosis and subsequently increased apoptosis. Time-lapse imaging showed that cisplatinum strongly induced cell-cycle arrest in the S/G2 phase in HeLa-FUCCI cells. Caffeine overcame the cell-cycle arrest induced by cisplatinum, thereby increasing its efficacy, since cisplatinum is ineffective against quiescent cells. The data in this report indicate that caffeine modulates the cell cycle in cancer cells, thereby enhancing efficacy of cell-cycle-dependent anticancer drugs such as cisplatinum.
authors.affiliation: AntiCancer, Inc., San Diego, California; Department of Surgery, University of California, San Diego, San Diego, California; Department of Orthopedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Miwa
authors.forename: Shuya
authors.initials: S
authors.lastname: Yano
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Tome
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Sugimoto
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hiroshima
authors.forename: Fuminari
authors.initials: F
authors.lastname: Uehara
authors.forename: Sumiyuki
authors.initials: S
authors.lastname: Mii
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kimura
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Elena V
authors.initials: EV
authors.lastname: Efimova
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: D017209:Apoptosis / Q000187:drug effects*; D002110:Caffeine / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004347:Drug Interactions; D006801:Humans; D018613:Microscopy, Confocal; D008938:Mitosis / Q000187:drug effects*
chemical_list: D002110:Caffeine; D002945:Cisplatin
keywords: APOPTOSIS; CAFFEINE; CELL CYCLE; CISPLATINUM; FLUORESCENCE IMAGING; FUCCI; GFP; MITOSIS; MODULATION; OSTEOSARCOMA; RFP