title: Mesenchymal stem cells are sensitive to treatment with kinase inhibitors and ionizing radiation.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) can regenerate damaged tissues and may therefore be of importance for normal tissue repair after cancer treatment. Small molecule receptor kinase inhibitors (RKIs) have recently been introduced into cancer treatment. However, the influence of these drugs-particularly in combination with radiotherapy-on the survival of MSCs is largely unknown.
  
  
  METHODS
  The sensitivity of human primary MSCs from healthy volunteers and primary human fibroblast cells to small molecule kinase inhibitors of the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ) receptors, as well to inhibitors of c-Kit, was examined in combination with ionizing radiation (IR); cell survival and proliferation were assessed. Expression patterns of different kinase receptors and ligands were investigated using gene arrays.
  
  
  RESULTS
  MSCs were highly sensitive to the tyrosine kinase inhibitors SU14816 (imatinib) and SU11657 (sunitinib), but showed only moderate sensitivity to the selective TGFβ receptor 1 inhibitor LY2109761. Primary adult human fibroblasts were comparably resistant to all three inhibitors. The addition of IR had an additive or supra-additive effect in the MSCs, but this was not the case for differentiated fibroblasts. Proliferation was markedly reduced in MSCs following kinase inhibition, both with and without IR. Gene expression analysis revealed high levels of the PDGF α and β receptors, and lower levels of the TGFβ receptor 2 and Abl kinase. IR did not alter the expression of kinase receptors or their respective ligands in either MSCs or adult fibroblasts.
  
  
  CONCLUSIONS
  These data show that MSCs are highly sensitive to RKIs and combination treatments incorporating IR. Expression analyses suggest that high levels of PDGF receptors may contribute to this effect.
authors.affiliation: Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany, n.nicolay@dkfz.de.
authors.forename: Nils H
authors.initials: NH
authors.lastname: Nicolay
authors.forename: Eva
authors.initials: E
authors.lastname: Sommer
authors.forename: Ramon Lopez
authors.initials: RL
authors.lastname: Perez
authors.forename: Ute
authors.initials: U
authors.lastname: Wirkner
authors.forename: Tilman
authors.initials: T
authors.lastname: Bostel
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.forename: Michael
authors.initials: M
authors.lastname: Lahn
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.forename: Rainer
authors.initials: R
authors.lastname: Saffrich
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011829:Radiation Dosage; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D017479:Receptors, Platelet-Derived Growth Factor