title: Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel.
abstract: Polo-like kinase 1 (PLK1), a serine/threonine kinase and an oncogene, is crucial in regulating cell cycle progression. PLK1 also has been demonstrated as a potential target of osteosarcoma (OS) by using short hairpin RNA libraries in lentiviral vectors for screening of protein kinase. In preclinical studies, GSK461364, a potent and selective ATP-competitive PLK1 inhibitor, showed antiproliferative activity against multiple tumor cell lines. In the present study, we evaluated the expression level of PLK1 in OS and explored the cytotoxic mechanism of GSK461364 against OS. PLK1 was significantly overexpressed in OS compared with normal osteoblasts and other types of sarcoma. GSK461364 inhibited PLK1 and caused mitotic arrest by inducing G2/M arrest in OS cells. Moreover, GSK461364 exerted a cytotoxic effect by inducing apoptosis in OS, and induced cellular senescence in OS cell lines, as indicated by an increased senescence-associated β-galactosidase activity and enhanced DcR2 and interleukin-1α expression. In addition, we demonstrated a synergistic cytotoxic effect of GSK461364 and paclitaxel, possibly resulting from combined mitotic arrest. In conclusion, the present study revealed that PLK1 was overexpressed in OS and that GSK461364 exerted its cytotoxic effect on OS by inducing mitotic arrest and subsequent apoptosis and induced cellular senescence; therefore, senescence-associated markers can be used as treatment biomarkers, and a combination of GSK461364 and paclitaxel can potentially treat OS.
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Yi-Sheng
authors.initials: YS
authors.lastname: Chou
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Chueh-Chuan
authors.initials: CC
authors.lastname: Yen
authors.affiliation: Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Yung-Chan
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Yao-Shan
authors.initials: YS
authors.lastname: Wen
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Ke
authors.affiliation: Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Jir-You
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
authors.affiliation: Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Tain-Hsiung
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Chien-Lin
authors.initials: CL
authors.lastname: Liu
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D017209:Apoptosis; D001562:Benzimidazoles / Q000737:chemistry*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D016922:Cellular Senescence; D019295:Computational Biology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005434:Flow Cytometry; D006801:Humans; D008938:Mitosis; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism*; D017239:Paclitaxel / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry*; D001616:beta-Galactosidase / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D000255:Adenosine Triphosphate; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D013876:Thiophenes; D001616:beta-Galactosidase; D000097869:Polo-Like Kinase 1; C561573:GSK 461364