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.
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.
Cancer Lett. 2016 Apr 28;374(1):75-84. doi: 10.1016/j.canlet.2016.02.007. Epub 2016 Feb 11.
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.
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.
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.
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.
抑制细胞拓扑异构酶已被证明是治疗某些癌症的有效方法，尽管骨髓毒性往往很高。虽然间充质干细胞（MSCs）在骨髓稳态和再生中的作用已得到充分证实，但拓扑异构酶抑制剂抗癌药物的作用仍知之甚少。
用拓扑异构酶 I 抑制剂伊立替康或拓扑异构酶 II 抑制剂依托泊苷处理人骨髓间充质干细胞，并测量其存活和凋亡水平。评估拓扑异构酶抑制对细胞形态、黏附和迁移能力以及分化能力的影响。此外，还研究了个体 DNA 双链断裂修复途径在间充质干细胞中的作用，作为其对拓扑异构酶抑制剂产生耐药性的潜在细胞机制。
人骨髓间充质干细胞对拓扑异构酶 I 和 II 抑制剂相对耐药，其存活水平与分化成纤维细胞相当。伊立替康或依托泊苷处理对人 MSCs 的细胞黏附、迁移能力、表面标志物表达或凋亡诱导没有显著影响。在高剂量伊立替康或依托泊苷暴露后，间充质干细胞的分化能力仍被发现得以保留。间充质干细胞能够通过非同源末端连接和同源重组途径有效修复拓扑异构酶抑制剂诱导的 DNA 双链断裂。
我们的数据表明人 MSCs 具有拓扑异构酶耐药表型，这至少部分归因于这些抗癌药物引起的干细胞有效去除 DNA 损伤的能力。观察到的间充质干细胞耐药性需要进一步研究这些细胞作为治疗拓扑异构酶抑制剂诱导的骨髓损伤的潜在治疗选择。
