Uncoupling DNA damage from chromatin damage to detoxify doxorubicin

The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanismof anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.Therapeutic cell differentiatio

3D morphology of the petal-like precipitates in Cu-Fe alloys: Experimental study and phase field modelling

International audiencePrecipitation hardening is a well-known phenomenon which is widely harnessed in alloy design strategy. In particular, the microstructural features such as shape, size, precipitate number density and volume fraction determine the mechanical behaviour of materials. During service, the morphology of precipitates sometimes achieves a complex 3D shape upon displaying branching and/or splitting patterns. Unfortunately, the detailed information about this intricate morphology cannot be retrieved through traditional experimental techniques based on 2D visualization. Here, we report the implementation of a 3D analysis technique combining Focused Ion Beam (FIB) and Scanning Electron Microscopy (SEM) tomography to visualize the atypical petal-like morphology of Fe-rich precipitates in a Cu-Fe alloy. Using Phase-Field modelling (PFM), we identify the mechanism responsible for the unusual morphologies of Fe-rich particles. Our work highlights the significance of 3D characterization of precipitates and provides a fascinating pathway for refining understanding of precipitation mechanisms in metals and alloys

Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin

DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. Here we identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage response, is also evicted by anthracyclines, and H2AX eviction is associated with attenuated DNA repair. Histone eviction deregulates the transcriptome in cancer cells and organs such as the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in patients. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription, side effects and cancer therapy