title: Impact of Polo-like kinase 1 inhibitors on human adipose tissue-derived mesenchymal stem cells.
abstract: Polo-like kinase 1 (Plk1) has been established as one of the most promising targets for molecular anticancer intervention. In fact, various Plk1 inhibitors have been identified and characterized. While the data derived from the bench are prospective, the clinical outcomes are less encouraging by showing modest efficacy. One of the explanations for this discrepancy could be unintendedly targeting of non-malignant cells by Plk1 inhibitors. In this work, we have addressed the effect of Plk1 inhibition in adipose tissue-derived mesenchymal stem cells (ASCs). We show that both visceral and subcutaneous ASCs display monopolar spindles, reduced viability and strong apoptosis induction upon treatment with BI 2536 and BI 6727, the Plk1 kinase domain inhibitors, and with Poloxin, the regulatory Polo-box domain inhibitor. While Poloxin triggers quickly apoptosis, BI 2536 and BI 6727 result in mitotic arrest in ASCs. Importantly, survived ASCs exhibit DNA damage and a pronounced senescent phenotype. In addition, Plk1 inhibition impairs ASCs' motility and homing ability. These results show that Plk1 inhibitors target slowly proliferating ASCs, an important population of anti-inflammation and immune modulation. The toxic effects on primary cells like ASCs could be partially responsible for the reported moderate antitumor activity in patients treated with Plk1 inhibitors.
authors.affiliation: Department of Gynecology and Obstetrics, School of Medicine, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ritter
authors.affiliation: Department of Gynecology and Obstetrics, School of Medicine, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Friemel
authors.affiliation: Department of Gynecology and Obstetrics, School of Medicine, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Nina-Naomi
authors.initials: NN
authors.lastname: Kreis
authors.affiliation: Department of Gynecology and Obstetrics, School of Medicine, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Louwen
authors.affiliation: Department of Gynecology and Obstetrics, School of Medicine, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
authors.forename: Juping
authors.initials: J
authors.lastname: Yuan
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
chemical_list: D001565:Benzoates; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D011809:Quinones; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C541363:BI 6727; C569433:poloxin
keywords: Plk1 inhibitors; adipose tissue-derived stem cell; apoptosis; mitotic arrest; senescence