Time-dependent onset of cellular senescence in response to carbon ions: implications for hadrontherapy

Stress-induced premature senescence (SIPS) is increasingly attracting interest as a cellular response to generalized sublethal stimuli, which include ionizing radiation (IR). Its timing can be modulated by the nature of the toxic agent while its underlying molecular mechanisms are not clear. Low doses of IR have been shown to induce SIPS in vitro in cell lines such as fibroblasts, this phenomenon being accompanied by premature differentiation. For the first time, here we demonstrate the occurrence of ectopic cellular senescence in human endothelial cells and its correlation with shortening of mean telomere length as assessed by Interphase Quantitative (IQ)-FISH. Carbon ions from the plateau region and from the Spread-Out Bragg Peak (SOBP), of interest for normal tissue and tumour vasculature hadrontherapy effects respectively, were accelerated at GSI (Darmstadt). Clonogenically iso-effective doses of low-LET radiation were used as reference. In our hands, the senescent phenotype was found to occur at early times post irradiation and was effectively induced by doses as low as 0.1-0.5 Gy of carbon ions. A persistent occurrence of senescing cells was found also in SOBP-irradiated cells, although at a lesser extent but despite the higher cell lethality known to be induced in SOBP. Mean length of telomeres, whose temporal stability is critical for maintenance of genomic stability and suppression of carcinogenesis, shows a reduction which is inversely related to LET, suggesting telomere length as a driving mechanism for SIPS after low LET irradiation but of no apparent relevance for carbon ion-induced senescence. These results will be discussed in relation to their implications for normal tissue adverse effects as well as desirable tumor vasculature impairment following hadrontherapy