E eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicinBaoxu Pang1,, Xiaohang Qiao1,, Lennert Janssen1, Arno Velds2, Tom Groothuis1, Ron Kerkhoven2, Marja Nieuwland2, Huib Ovaa1, Sven Rottenberg3, Olaf van Tellingen4, Jeroen Janssen6, Peter Huijgens6, Wilbert Zwart5 Jacques NeefjesDNA topoisomerase II inhibitors are a major class of Cancer chemotherapeutics, that are thought to remove cancer cells by inducing DNA double-strand breaks. Right here we identify a novel activity for the Actin Remodelingand Cell Migration Inhibitors Reagents anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal locations. We show that anthracyclines market histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, that is a key element of your DNA damage response, can also be evicted by anthracyclines, and H2AX eviction is associated with attenuated DNA repair. Histone eviction Cilastatin (sodium) Bacterial deregulates the transcriptome in cancer cells and organs which include the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in sufferers. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with crucial consequences for DNA damage responses, epigenetics, transcription, unwanted side effects and cancer therapy.1 Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, The Netherlands. 2 Central Genomic Facility, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, The Netherlands. 3 Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, The Netherlands. four Division of Diagnostic Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, The Netherlands. five Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, The Netherlands. 6 Department of Hematology, VU University Healthcare Center, Boelelaan 1117, Amsterdam 1081 HV, The Netherlands. These authors contributed equally to this perform. Correspondence and requests for materials need to be addressed to J.N. (e-mail: [email protected]).NATURE COMMUNICATIONS | four:1908 | DOI: 10.1038/ncomms2921 | nature.com/naturecommunications2013 Macmillan Publishers Limited. All rights reserved.ARTICLEany essential signalling pathways driving cancer have already been identified and yielded therapeutic agents targeting these pathways with varying success1,two. Although such agents usually have fewer side effects compared with conventional anticancer drugs, tumour resistance is usually swift. Consequently, traditional chemotherapy remains standard practice in cancer treatment, specifically for aggressive tumours like acute myeloid leukaemia (AML). Additionally, modern day cancer treatment increasingly combines conventional chemotherapeutic drugs with modern targeted anticancer drugs. Doxorubicin (Doxo; also termed Adriamycin) is one particular of these `older’ conventional drugs3. Doxo is extensively utilised as a first-choice anticancer drug for many tumours and is one of the most successful anticancer drugs developed4,5. Millions of cancer patients have been treated with Doxo, or its variants daunorubicin (Daun) and idarubicin (Ida)six. Currently these drugs are included in 500 reported trials worldwide to discover improved combinations (ClinicalTrials.gov. http://clinicaltrials.gov/ ct2/resultsterm 22doxorubicin 22 OR 22adriamycin 22 OR 22daunorubicin 22 OR 22Idarubicin 22 recr O.
