Inserm U563, Institut Claudius‐Régaud, Toulouse, France. Laboratoire d‘hématologie, centre hospitalier universitaire Purpan, Toulouse, France. Service d‘hématologie, centre hospitalier universitaire Purpan, Toulouse, France.
Previous studies have documented that genotoxic agents, such as drugs and γ‐ or UV‐irradiation, activate various cellular responses, including mitotic cell death, apoptosis or transient cell cycle block depending on the level of DNA damage and the functionality of the apoptotic machinery. More recently, it has been described that sublethal DNA damages may also induce, at least in some cellular models, cellular senescence (Stress‐Induced Premature Senescence\SIPS) both
in vitro and
in vivo. SIPS cellular phenotype resembles to that of replicative senescence, including progressive morphological changes, prolonged and irreversible growth arrest, loss of clonogenic potential, telomere shortening, and acid β‐galactosidase overexpression. However, in contrast to replicative senescence, telomerase stimulation does not protect cells from SIPS, suggesting that SIPS is more likely related to telomere disorganization rather telomere shortening
per se. Both induction and maintain of SIPS appear to be under control of critical protein regulators, including p53, p21
WAF1, INK4 gene products, all being also involved in drug‐induced apoptosis. This observation suggests a link between apoptosis and SIPS, the latter being activated when apoptosis is inhibited. Importantly, p53 mutation or INK4 gene silencing, as occasionally described in leukemias and lymphomas, abrogate induction of senescence and confer drug resistance. SIPS is accompanied by intense genetic instability with gross chromosomal abnormalities possibly due to illegitimate DNA recombination. Accumulation of genetic alterations ultimately results in cell death, sometimes after a very long period of time, whereas, upon loss of control, some cells may eventually exit from senescence and recover growth capacity. Finally, whereas senescence has been underestimated in the context of anti‐tumor pharmacology, it appears now that SIPS should profoundly influence our vision of so‐called stable (or residual) disease, secondary drug resistance, and drug‐induced mutagenesis.