Oncotarget

Research Papers:

Cisplatin radiosensitizes radioresistant human mesenchymal stem cells

Alexander Rühle, Ramon Lopez Perez, Christin Glowa, Klaus-Josef Weber, Anthony D. Ho, Jürgen Debus, Rainer Saffrich, Peter E. Huber and Nils H. Nicolay _

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Oncotarget. 2017; 8:87809-87820. https://doi.org/10.18632/oncotarget.21214

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Abstract

Alexander Rühle1,2, Ramon Lopez Perez1,2, Christin Glowa1,2, Klaus-Josef Weber2,3, Anthony D. Ho4, Jürgen Debus2,3, Rainer Saffrich4, Peter E. Huber1,2,3 and Nils H. Nicolay1,2,3

1Department of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

2Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology, 69120 Heidelberg, Germany

3Department of Radiation Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany

4Department of Hematology and Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany

Correspondence to:

Nils H. Nicolay, email: n.nicolay@dkfz.de

Keywords: mesenchymal stem cells, cisplatin, radiotherapy, DNA double-strand breaks, radiosensitization

Received: July 19, 2017     Accepted: August 17, 2017     Published: September 23, 2017

ABSTRACT

Cisplatin-based chemo-radiotherapy is widely used to treat cancers with often severe therapy-associated late toxicities. While mesenchymal stem cells (MSCs) were shown to aid regeneration of cisplatin- or radiation-induced tissue lesions, the effect of the combined treatment on the stem cells remains unknown. Here we demonstrate that cisplatin treatment radiosensitized human bone marrow-derived MSCs in a dose-dependent manner and increased levels of radiation-induced apoptosis. However, the defining stem cell properties of MSCs remained largely intact after cisplatin-based chemo-radiation, and stem cell motility, adhesion, surface marker expression and the characteristic differentiation potential were not significantly influenced. The increased cisplatin-mediated radiosensitivity was associated with a cell cycle shift of MSCs towards the radiosensitive G2/M phase and increased residual DNA double-strand breaks. These data demonstrate for the first time a dose-dependent radiosensitization effect of MSCs by cisplatin. Clinically, the observed increase in radiation sensitivity and subsequent loss of regenerative MSCs may contribute to the often severe late toxicities observed after cisplatin-based chemo-radiotherapy in cancer patients.


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