title: Selective methioninase-induced trap of cancer cells in S/G2 phase visualized by FUCCI imaging confers chemosensitivity.
abstract: A major impediment to the response of tumors to chemotherapy is that the large majority of cancer cells within a tumor are quiescent in G0/G1, where cancer cells are resistant to chemotherapy. To attempt to solve this problem of quiescent cells in a tumor, cancer cells were treated with recombinant methioninase (rMETase), which selectively traps cancer cells in S/G2. The cell cycle phase of the cancer cells was visualized with the fluorescence ubiquitination-based cell cycle indicator cell cycle indicator (FUCCI). At the time of rMETase-induced S/G2-phase blockage, identified by the cancer cells' green fluorescence by FUCCI imaging, the cancer cells were administered S/G2-dependent chemotherapy drugs, which interact with DNA or block DNA synthesis such as doxorubicin, cisplatin, or 5-fluorouracil. Treatment of cancer cells with drugs only, without rMETase-induced S/G2 phase blockage, led to the majority of the cancer-cell population being blocked in G0/G1 phase, identified by the cancer cells becoming red fluorescent in the FUCCI system. The G0/G1 blocked cells were resistant to the chemotherapy. In contrast, trapping of cancer cells in S/G2 phase by rMETase treatment followed by FUCCI-imaging-guided chemotherapy was highly effective in killing the cancer cells.
authors.affiliation: AntiCancer, Inc, San Diego, CA. Department of Surgery, University of California, San Diego, CA. Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Shuya
authors.initials: S
authors.lastname: Yano
authors.affiliation: AntiCancer, Inc, San Diego, CA.
authors.forename: Shukuan
authors.initials: S
authors.lastname: Li
authors.affiliation: AntiCancer, Inc, San Diego, CA.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Han
authors.affiliation: AntiCancer, Inc, San Diego, CA.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Surgery, University of California, San Diego, CA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: AntiCancer, Inc, San Diego, CA. Department of Surgery, University of California, San Diego, CA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D013437:Carbon-Sulfur Lyases / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D011994:Recombinant Proteins / Q000008:administration & dosage; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase