title: Mesenchymal stem cells exhibit resistance to topoisomerase inhibition.
abstract: BACKGROUND
  Inhibition of cellular topoisomerases has been established as an effective way of treating certain cancers, albeit with often high levels of toxicity to the bone marrow. While the involvement of mesenchymal stem cells (MSCs) in bone marrow homeostasis and regeneration has been well established, the effects of topoisomerase-inhibiting anticancer agents remain largely unknown.
  
  
  METHODS
  Human bone marrow MSCs were treated with topoisomerase I inhibitor irinotecan or topoisomerase II inhibitor etoposide, and survival and apoptosis levels were measured. The influence of topoisomerase inhibition on cellular morphology, adhesion and migration potential and the ability to differentiate was assessed. Additionally, the role of individual DNA double-strand break repair pathways in MSCs was investigated as a potential cellular mechanism of resistance to topoisomerase inhibitors.
  
  
  RESULTS
  Human bone marrow MSCs were found relatively resistant to topoisomerase I and II inhibitors and show survival levels comparable to these of differentiated fibroblasts. Treatment with irinotecan or etoposide did not significantly influence cellular adhesion, migratory ability, surface marker expression or induction of apoptosis in human MSCs. The ability to differentiate was found preserved in MSCs after exposure to high doses of irinotecan or etoposide. MSCs were able to efficiently repair DNA double-strand breaks induced by topoisomerase inhibitors both by non-homologous end joining and homologous recombination pathways.
  
  
  CONCLUSIONS
  Our data demonstrate a topoisomerase-resistant phenotype of human MSCs that may at least in part be due to the stem cells' ability to efficiently remove DNA damage caused by these anticancer agents. The observed resistance of MSCs warrants further investigation of these cells as a potential therapeutic option for treating topoisomerase inhibitor-induced bone marrow damage.
authors.affiliation: Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Molecular and Radiation Oncology, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: n.nicolay@dkfz.de.
authors.forename: Nils H
authors.initials: NH
authors.lastname: Nicolay
authors.affiliation: Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Molecular and Radiation Oncology, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rühle
authors.affiliation: Department of Molecular and Radiation Oncology, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Ramon Lopez
authors.initials: RL
authors.lastname: Perez
authors.affiliation: Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Thuy
authors.initials: T
authors.lastname: Trinh
authors.affiliation: Department of Molecular and Radiation Oncology, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Sonevisay
authors.initials: S
authors.lastname: Sisombath
authors.affiliation: Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Klaus-Josef
authors.initials: KJ
authors.lastname: Weber
authors.affiliation: Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.affiliation: Department of Hematology and Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.affiliation: Department of Hematology and Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Saffrich
authors.affiliation: Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Molecular and Radiation Oncology, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D000077146:Irinotecan; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D000077146:Irinotecan; D002166:Camptothecin
keywords: Bone marrow toxicity; Chemotherapy; Etoposide; Irinotecan; Mesenchymal stem cells; Topoisomerase inhibitor