ABSTRACT
Major anti-cancer treatment regimes are based on the use of agents inducing DNA damage, such as ionizing radiation or various chemotherapeutic drugs. However, these treatments inevitably aff ect the stroma surrounding the tumor. As DNA damage can provoke accelerated senescence, several studies have focus on the biological eff ect of chemotherapeutic drugs on stromal fi broblasts. Doxorubicin and etoposide are topoisomerase II poisons that provoke DNA double stand breaks (DSBs) and single stand breaks (SSBs) (Vamvakas et al. 1997). Both drugs can induce a senescent-like permanent growth arrest in normal human fi broblasts (Robles et al. 1999). On the other hand, camptothecin, a topoisomerase I poison that causes SSBs which can be converted to DSBs when the cells traverse S phase (Ryan et al. 1991; Chen and Liu 1994), is unable to provoke senescence in these cells (Robles et al. 1999). However cisplatin, another agent causing SSBs that can also lead to DSBs, can induce premature senescence in human fi broblasts with a concomitant reduction of gap junctions (Zhao et al. 2004). Busulfan is an alkylating agent that can cause DNA-DNA and DNA-protein cross-links that may trigger a DNA damage response (Iwamoto et al. 2004; Mertins et al. 2004), and in contrast to the majority of chemotherapeutic drugs it aff ects mostly slow proliferating or non-proliferating cells (Probin et al. 2006). Busulfan was also found to provoke premature senescence in human fi broblasts, but in a mode independent of p53 activation (Probin et al. 2006). In contrast, busulfan depletes intracellular glutathione and increases reactive oxygen species, leading to the activation of ERK and p38 MAPK. Incubation with the potent antioxidant N-acetyl-cysteine can eff ectively attenuate busulfan-mediated premature senescence (Probin et al. 2007). Finally taxol, a chemotherapeutic agent that promotes the assembly of tubulin heterodimers and inhibits their depolymerization, was found to promote premature senescence of human stromal fi broblasts (our unpublished observations). Th is is probably due to the formation of reactive oxygen species and to alterations of mitochondrial membrane permeability (Varbiro et al. 2001). Ionizing radiation by producing DSBs and SSBs in the DNA is used in radiotherapy as to produce cancer cells’ arrest and/or death. It also aff ects stromal cells and several studies have shown that it can provoke premature senescence (Naka et al. 2004; Suzuki et al. 2006; Papadopoulou and Kletsas 2011). Th is is achieved by the immediate activation of the
ATM-Chk2-p53-p21WAF1-pRb axis and the delayed overexpression and phosphorylation of p16INK4a and p38 MAPK, respectively.
