title: Polo-box domain inhibitor poloxin activates the spindle assembly checkpoint and inhibits tumor growth in vivo.
abstract: Polo-like kinase 1 (Plk1) is widely established as one of the most promising targets in oncology. Although the protein kinase domain of Plk1 is highly conserved, the polo-box domain (PBD) of Plk1 provides a much more compelling site to specifically inhibit the localization and target binding of Plk1. We recently identified, via fluorescence polarization assay, the natural product derivative, Poloxin, as the first small-molecule inhibitor specifically targeting the function of the Plk1 PBD. In this study, we characterized its mitotic phenotype and its function in vitro and in vivo. Poloxin induces centrosome fragmentation and abnormal spindle and chromosome misalignment, which activate the spindle assembly checkpoint and prolong mitosis. Notably, centrosomal fragmentation induced by Poloxin is partially attributable to dysfunctional Kizuna, a key substrate of Plk1 at centrosomes. Moreover, Poloxin strongly inhibits proliferation of a panel of cancer cells by inducing mitotic arrest, followed by a surge of apoptosis. More important, we report, for the first time to our knowledge, that the PBD inhibitor, Poloxin, significantly suppresses tumor growth of cancer cell lines in xenograft mouse models by lowering the proliferation rate and triggering apoptosis in treated tumor tissues. The data highlight that targeting the PBD by Poloxin is a powerful approach for selectively inhibiting Plk1 function in vitro and in vivo.
authors.affiliation: Department of Gynecology and Obstetrics, School of Medicine, J. W. Goethe-University, Frankfurt, Germany. yuan@em.uni-frankfurt.de
authors.forename: Juping
authors.initials: J
authors.lastname: Yuan
authors.forename: Mourad
authors.initials: M
authors.lastname: Sanhaji
authors.forename: Andrea
authors.initials: A
authors.lastname: Krämer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Reindl
authors.forename: Matthias
authors.initials: M
authors.lastname: Hofmann
authors.forename: Nina-Naomi
authors.initials: NN
authors.lastname: Kreis
authors.forename: Brigitte
authors.initials: B
authors.lastname: Zimmer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berg
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebhardt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D002877:Chromosomes, Human / Q000378:metabolism; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D051379:Mice; D009369:Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D001565:Benzoates; D016227:Benzoquinones; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011809:Quinones; D000097869:Polo-Like Kinase 1; C569433:poloxin; C003466:thymoquinone