The role of DNA damage and repair in decitabine-mediated apoptosis in multiple myeloma.
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.
Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium;
Ken
K
Maes
Eva
E
De Smedt
Miguel
M
Lemaire
Hendrik
H
De Raeve
Eline
E
Menu
Els
E
Van Valckenborgh
Steve
S
McClue
Karin
K
Vanderkerken
Elke
E
De Bruyne
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D000077209:Decitabine; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction
D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; C541788:quisinostat; D000077209:Decitabine; D001374:Azacitidine