Nils H Nicolay1, Alexander Rühle2, Ramon Lopez Perez3, Thuy Trinh4, Sonevisay Sisombath3, Klaus-Josef Weber4, Peter Schmezer5, Anthony D Ho6, Jürgen Debus4, Rainer Saffrich6, Peter E Huber7. 1. 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. 2. 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. 3. Department of Molecular and Radiation Oncology, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. 4. 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. 5. Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. 6. Department of Hematology and Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. 7. 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.
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. MATERIALS AND 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. CONCLUSION: 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.
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. MATERIALS AND METHODS:Humanbone 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:Humanbone 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. CONCLUSION: 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: Alexander Rühle; Ramon Lopez Perez; Bingwen Zou; Anca-Ligia Grosu; Peter E Huber; Nils H Nicolay Journal: Stem Cell Rev Rep Date: 2019-06 Impact factor: 5.739
Authors: Franziska Münz; Ramon Lopez Perez; Thuy Trinh; Sonevisay Sisombath; Klaus-Josef Weber; Patrick Wuchter; Jürgen Debus; Rainer Saffrich; Peter E Huber; Nils H Nicolay Journal: Sci Rep Date: 2018-01-10 Impact factor: 4.379
Authors: Nils H Nicolay; Alexander Rühle; Ramon Lopez Perez; Thuy Trinh; Sonevisay Sisombath; Klaus-Josef Weber; Anthony D Ho; Jürgen Debus; Rainer Saffrich; Peter E Huber Journal: Sci Rep Date: 2016-05-24 Impact factor: 4.379
Authors: Alexander Rühle; Ramon Lopez Perez; Christin Glowa; Klaus-Josef Weber; Anthony D Ho; Jürgen Debus; Rainer Saffrich; Peter E Huber; Nils H Nicolay Journal: Oncotarget Date: 2017-09-23
Authors: Ramon Lopez Perez; Jannek Brauer; Alexander Rühle; Thuy Trinh; Sonevisay Sisombath; Patrick Wuchter; Anca-Ligia Grosu; Jürgen Debus; Rainer Saffrich; Peter E Huber; Nils H Nicolay Journal: Sci Rep Date: 2019-12-27 Impact factor: 4.379