Transient chromatin decompaction by histone deacetylation inhibition preferentially radiosensitizes cancerous breast epithelial cells at lower radiation doses
Li, H.; Maben, C.; Pal, D.; Davern, S.; McCord, R. P.
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Radiation therapy plays a prominent role in breast cancer treatment, but the high doses of radiation damage both healthy and cancerous cells. Therefore, additional research is needed into combination therapies that could preferentially radiosensitize cancer cells compared to surrounding healthy tissue without causing deleterious side effects. Histone deacetylase inhibitor drugs (HDACis) have been tested as radiosensitizers in both basic research and clinical trials, but the long exposure usually used in these treatments and lack of examination of effects on matched healthy cells leave aspects of their mechanism of action unclear. Here, we show that transient (2 hour) trichostatin A (TSA) treatment of cancerous and non-tumorigenic breast epithelial cell lines increases immediate DNA damage and decreases long-term cell survival in both cell types at high radiation doses. At an intermediate radiation dose (1 Gy), however, TSA treatment selectively radiosensitizes the cancer as compared to the non-cancer cell line. The radiosensitizing action of short-term TSA treatment, which by itself has no impact on cell viability, suggests that chromatin decompaction is an important part of the mechanism of radiosensitization by HDACis.
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