Abstract
Compact chromatin is linked to a poor tumour prognosis and resistance to radiotherapy from photons. We investigated DNA damage induction and repair in the context of chromatin structure for densely ionising alpha radiation as well as its therapeutic potential. Chromatin opening by histone deacetylase inhibitor trichostatin A (TSA) pretreatment reduced clonogenic survival and increased γH2AX foci in MDA-MB-231 cells, indicative of increased damage induction by free radicals using gamma radiation. In contrast, TSA pretreatment tended to improve survival after alpha radiation while γH2AX foci were similar or lower; therefore, an increased DNA repair is suggested due to increased access of repair proteins. MDA-MB-231 cells exposed to fractionated gamma radiation (2 Gy × 6) expressed high levels of stem cell markers, elevated heterochromatin H3K9me3 marker, and a trend towards reduced clonogenic survival in response to alpha radiation. There was a higher level of H3K9me3 at baseline, and the ratio of DNA damage induced by alpha vs. gamma radiation was higher in the aggressive MDA-MB-231 cells compared to hormone receptor-positive MCF7 cells. We demonstrate that heterochromatin structure and stemness properties are induced by fractionated radiation exposure. Gamma radiation-exposed cells may be targeted using alpha radiation, and we provide a mechanistic basis for the involvement of chromatin in these effects.
Highlights
Resistance of tumours to radiotherapy and chemotherapy is a severe problem
Due to the noticeably different response in clonogenic survival and γH2AX foci number between gamma and alpha radiation, we suggest that double strand breaks (DSB) induction is prominent for gamma but is of minor importance for the action of alpha radiation in trichostatin A (TSA)-pretreated cells
TSA, we suggest that this phenomenon is mainly due to the ability of alpha radiation to go through chromatin and propose this as a biological basis for future evaluation of targeted alpha emitter therapy
Summary
Breast cancer is among the most common cancers in women, and survival has improved the last decades, the heterogeneity of the disease is large [1]. Half of all breast cancer patients receive photon radiotherapy, commonly as adjuvant therapy after surgery, the HER2 and triple negative subtypes are reported to respond less well than luminal cancers [1]. Apart from intrinsic factors such as DNA repair capacity that may influence cellular radiosensitivity [2], it is realised that, in cases where cell killing is insufficient, tumour cells acquire a radioresistant phenotype as a consequence of fractionated irradiation [3,4]. The mechanisms of this acquired radioresistance are not fully understood
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