Alpha Radiation as a Way to Target Heterochromatic and Gamma Radiation-Exposed Breast Cancer Cells

• Published in: Cells (Basel, Switzerland) Vol. 9; no. 5; p. 1165
• Main Authors: Svetličič, Maja, Bomhard, Anton, Sterr, Christoph, Brückner, Fabian, Płódowska, Magdalena, Lisowska, Halina, Lundholm, Lovisa
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.05.2020; MDPI
• Subjects: Acetylation; Alpha Particles; alpha radiation; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer therapies; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - radiation effects; Chromatin; Clone Cells; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Epidermal growth factor; Female; Free radicals; gamma radiation; Gamma Rays; Heterochromatin; Heterochromatin - radiation effects; Histone deacetylase; Histones - metabolism; Humans; Hydroxamic Acids - pharmacology; Lysine - metabolism; Medical prognosis; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - radiation effects; Photons; Proteins; Radiation Exposure; Radiation therapy; Spheroids, Cellular - drug effects; Spheroids, Cellular - pathology; Spheroids, Cellular - radiation effects; Stem cells; Trichostatin A; Tumors; α Radiation; γ Radiation; gamma radiation; breast cancer; alpha radiation; chromatin; DNA damage
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9051165

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.