Abstract
Despite prominent role of radiotherapy in lung cancer management, there is an urgent need for strategies increasing therapeutic efficacy. Reversible epigenetic changes are promising targets for combination strategies using HDAC inhibitors (HDACi).Here we evaluated on two NSCLC cell lines, the antitumor effect of abexinostat, a novel pan HDACi combined with irradiation in vitro in normoxia and hypoxia, by clonogenic assays, demonstrating that abexinostat enhances radiosensitivity in a time dependent way with mean SER10 between 1.6 and 2.5 for A549 and H460. We found, by immunofluorescence staining, flow cytometry assays and western blotting, in abexinostat treated cells, increasing radio-induced caspase dependent apoptosis and persistent DNA double-strand breaks associated with decreased DNA damage signalling and repair. Interestingly, we demonstrated on nude mice xenografts that abexinostat potentiates tumor growth delay in combined modality treatments associating not only abexinostat and irradiation but also when adding cisplatin.Altogether, our data demonstrate in vitro and in vivo anti-tumor effect potentiation by abexinostat combined with irradiation in NSCLC. Moreover, our work suggests for the first time to our knowledge promising triple combination opportunities with HDACi, irradiation and cisplatin which deserves further investigations and could be of major interest in the treatment of NSCLC.
Highlights
Epigenetics is a promising field of research with growing preclinical and clinical data providing new avenues for cancer treatment
Abundant pre-clinical studies and early clinical trials have shown a promising anti-tumor effect of Histone deacetylases (HDACs) inhibitors (HDACi) alone or in combination with chemotherapy agents linked with an induced alteration in DNA repair capacity [2628]
Rapidly expanding pre-clinical in vitro and in vivo data have shown a radiosensitizing effect of various HDACi in different tumor cells explained by www.impactjournals.com/oncotarget changes is chromatin conformation or reduced DNA repair capacity when combined with irradiation [3]
Summary
Epigenetics is a promising field of research with growing preclinical and clinical data providing new avenues for cancer treatment. In the absence of DNA sequence alteration, gene expression driven by epigenetic changes is crucial to tumor onset and progression [1,2,3]. Epigenetic changes such as acetylation, methylation, phosphorylation, ubiquitination and sumoylation lead to modifications of the structure of nucleosomes impacting chromatin condensation and transcription [1, 4, 5]. Histone deacetylases (HDACs) remove acetyl groups from histones, leading to a more compact form of chromatin, favoring gene expression patterns that promote tumor development. Some are either already approved in clinic as vorinostat
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