title: Polo-like kinase inhibitor Ro5203280 has potent antitumor activity in nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma is a cancer with its highest prevalence among the southern Chinese and is rare elsewhere in the world. The main treatment modalities include chemotherapy and radiotherapy. However, tumor chemoresistance often limits the efficacy of nasopharyngeal carcinoma treatment and reduces survival rates. Thus, identifying new selective chemotherapeutic drugs for nasopharyngeal carcinoma treatment is needed. In this current study, the antitumor efficacy of a polo-like kinase inhibitor, Ro5203280, was investigated. Ro5203280 induces tumor suppression both in vitro and in vivo. An inhibitory effect was observed with the highly proliferating cancer cell lines tested, but not with the nontumorigenic cell line. Real-time cell proliferation and fluorescence-activated cell sorting (FACS) analysis, together with immunohistochemical (IHC), immunofluorescence, and Annexin V staining assays, were used to evaluate the impact of drug treatment on cell cycle and apoptosis. Ro5203280 induces G2-M cell-cycle arrest and apoptosis. Western blotting shows it inhibits PLK1 phosphorylation and downregulates the downstream signaling molecule, Cdc25c, and upregulates two important mitosis regulators, Wee1 and Securin, as well as the DNA damage-related factor Chk2 in vitro and in vivo. In vivo tumorigenicity assays with Ro5203280 intravenous injection showed its potent ability to inhibit tumor growth in mice, with no observable signs of toxicity. These findings suggest the potential usefulness of Ro5203280 as a chemotherapeutic targeting drug for nasopharyngeal carcinoma treatment.
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: Arthur Kwok Leung
authors.initials: AK
authors.lastname: Cheung
authors.forename: Joseph Chok Yan
authors.initials: JC
authors.lastname: Ip
authors.forename: Hong Lok
authors.initials: HL
authors.lastname: Lung
authors.forename: Jim Zhen
authors.initials: JZ
authors.lastname: Wu
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Maria Li
authors.initials: ML
authors.lastname: Lung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002277:Carcinoma; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018797:Cell Cycle Proteins; D006574:Heterocyclic Compounds, 2-Ring; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C587440:Ro5203280