Abstract
In the quest for more effective radiation treatment options that can improve both cell killing and healthy tissue recovery, combined radiation therapies are lately in the spotlight. The molecular response to a combined radiation regime where exposure to an initial low dose (priming dose) of ionizing radiation is administered prior to a subsequent higher radiation dose (challenging dose) after a given latency period have not been thoroughly explored. In this study we report on the differential response to either a combined radiation regime or a single challenging dose both in mouse in vivo and in human ex vivo thymocytes. A differential cell cycle response including an increase in the subG1 fraction on cells exposed to the combined regime was found. Together with this, a differential protein expression profiling in several pathways including cell cycle control (ATM, TP53, p21CDKN1A), damage response (γH2AX) and cell death pathways such as apoptosis (Cleaved Caspase-3, PARP1, PKCδ and H3T45ph) and ferroptosis (xCT/GPX4) was demonstrated. This study also shows the epigenetic regulation following a combined regime that alters the expression of chromatin modifiers such as DNMTs (DNMT1, DNMT2, DNMT3A, DNMT3B, DNMT3L) and glycosylases (MBD4 and TDG). Furthermore, a study of the underlying cellular status six hours after the priming dose alone showed evidence of retained modifications on the molecular and epigenetic pathways suggesting that the priming dose infers a “radiation awareness phenotype” to the thymocytes, a sensitization key to the differential response seen after the second hit with the challenging dose. These data suggest that combined-dose radiation regimes could be more efficient at making cells respond to radiation and it would be interesting to further investigate how can these schemes be of use to potential new radiation therapies.
Highlights
In the quest for more effective radiation treatment options that can improve both cell killing and healthy tissue recovery, combined radiation therapies are lately in the spotlight
Using in vivo mouse models, us and others found that a combined regime of radiation, where the priming low dose was administered as an acute dose[9] or chronic exposure[10], could exert a differential effect on apoptosis in cells of the lymphoid line by regulating expression of genes involved in cell death control
Understanding the activation of the damage and cell cycle control pathways to either a single dose or a combined regime of radiation, would be pivotal at getting an overall picture of the response to a combined scheme and whether or not this regime could be more useful at cell killing and maintaining healthy tissue homeostasis than fractionating the total treatment dose into challenging doses alone
Summary
In the quest for more effective radiation treatment options that can improve both cell killing and healthy tissue recovery, combined radiation therapies are lately in the spotlight. Using in vivo mouse models, us and others found that a combined regime of radiation, where the priming low dose was administered as an acute dose[9] or chronic exposure[10], could exert a differential effect on apoptosis in cells of the lymphoid line by regulating expression of genes involved in cell death control This suggests that more information is needed on which cell death mechanisms are induced after a combined radiation treatment and how can they be key to the betterment of radiation therapies. Understanding these epigenetic mechanisms within the combined regime will help understanding the overall response of thymocytes and the mechanism of transmission of information between the two doses in a combined radiation therapy
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