Time dependent modulation of tumor radiosensitivity by a pan HDAC inhibitor: abexinostat
Radiotherapy plays a critical role in the treatment of lung cancer, yet there remains an urgent need for strategies that can enhance its therapeutic efficacy. Reversible epigenetic changes represent promising targets for combination therapies, particularly with histone deacetylase inhibitors (HDACi). In this study, we investigated the antitumor effects of abexinostat, a novel pan-HDACi, in combination with irradiation in two non-small cell lung cancer (NSCLC) cell lines, A549 and H460, both under normoxic and hypoxic conditions. Using clonogenic assays, we demonstrated that abexinostat enhances radiosensitivity in a time-dependent manner, with a mean sensitizer enhancement ratio (SER10) ranging from 1.6 to 2.5.
Further analysis through immunofluorescence, flow cytometry, and Western blotting revealed that abexinostat treatment increased radiation-induced, caspase-dependent apoptosis and led to persistent DNA double-strand breaks. This was associated with decreased DNA damage signaling and impaired DNA repair mechanisms. Notably, in nude mouse xenograft models, we observed that abexinostat potentiated tumor growth delay when combined with irradiation, and this effect was further enhanced by the addition of cisplatin.
Our findings provide strong evidence for the in vitro and in vivo antitumor activity of abexinostat in combination with irradiation in NSCLC. Moreover, this is the first study, to our knowledge, to suggest a promising triple combination of HDACi, radiation, and cisplatin, a strategy that warrants further investigation and could have significant therapeutic potential in NSCLC treatment.