The role of DNA damage and repair in decitabine-mediated apoptosis in multiple myeloma
Metrics: PDF 2665 views | HTML 2347 views | ?
Ken Maes1, Eva De Smedt1, Miguel Lemaire1, Hendrik De Raeve2, Eline Menu1, Els Van Valckenborgh1, Steve McClue3, Karin Vanderkerken1,* and Elke De Bruyne1,*
1 Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium;
2 Department of Pathology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium;
3 Oncology Translational Medicine, Janssen, Pharmaceutical Companies of Johnson & Johnson, Buckinghamshire, United Kingdom.
* These authors contributed equally
Elke De Bruyne, email:
Keywords: Multiple myeloma, DNA methyltransferase inhibitor, histone deacetylase inhibitor, DNA damage, DNA repair
Received: January 21, 2014 Accepted: March 21, 2014 Published: March 22, 2014
DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) are under investigation for the treatment of cancer, including the plasma cell malignancy multiple myeloma (MM). Evidence exists that DNA damage and repair contribute to the cytotoxicity mediated by the DNMTi decitabine. Here, we investigated the DNA damage response (DDR) induced by decitabine in MM using 4 human MM cell lines and the murine 5T33MM model. In addition, we explored how the HDACi JNJ-26481585 affects this DDR. Decitabine induced DNA damage (gamma-H2AX foci formation), followed by a G0/G1- or G2/M-phase arrest and caspase-mediated apoptosis. JNJ-26481585 enhanced the anti-MM effect of decitabine both in vitro and in vivo. As JNJ-26481585 did not enhance decitabine-mediated gamma-H2AX foci formation, we investigated the DNA repair response towards decitabine and/or JNJ-26481585. Decitabine augmented RAD51 foci formation (marker for homologous recombination (HR)) and/or 53BP1 foci formation (marker for non-homologous end joining (NHEJ)). Interestingly, JNJ-26481585 negatively affected basal or decitabine-induced RAD51 foci formation. Finally, B02 (RAD51 inhibitor) enhanced decitabine-mediated apoptosis. Together, we report that decitabine-induced DNA damage stimulates HR and/or NHEJ. JNJ-26481585 negatively affects RAD51 foci formation, thereby providing an additional explanation for the combinatory effect between decitabine and JNJ-26481585.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.