Cyclophosphamide induces premature senescence in normal human fibroblasts by activating MAP kinases.

Cellular senescence is induced by diverse mechanisms and is in turn mediated by multiple biochemical pathways. We found that cyclophosphamide sensitively inhibits the growth of normal human fibroblasts. Those growth arrested fibroblasts showed morphology similar to that of normally senesced cells and strongly expressed senescence-associated β-galactosidase. They also showed up regulation of senescence-associated genes and eventually lost their division potential. In addition, enhanced phosphorylation of MAP kinases was found in growth arrested cells, very similar to normally senesced cells. Collectively, these results suggest that cyclophosphamide uses signaling pathways similar to those that are active in replicative senescence, thereby leading to premature senescence.