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

Abstract

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.

Efficient induction of apoptosis by proteasome inhibitor: bortezomib in the human breast cancer cell line MDA-MB-231

“…It is a common programme that is activated by normal cells in response to various types of stress. It has been named ‘stress-induced premature senescence’ [19]. This type of senescence can act as a tumour suppressor in order to prevent damaged cells to multiply as well as a secondary outcome for cancer cells due to therapeutic treatments [16].…”

“…The term senescence was originally applied to the irreversible growth arrest of cells after prolonged proliferation under in vitro cell culture conditions. Now it has been extended to the irreversible proliferation arrest of cells caused by various stresses, including oxidative damage, telomere dysfunction, DNA damage and oncogene-induced senescence as well [17–19]. Tumour cells are exposed to many different external as well as internal sources of stress; therefore, the induction of senescence constitutes an important block to tumour progression [16].…”

Effects of Cyclophosphamide Pulse Therapy on the Clinical and Histopathological Findings, Particularly Crescent Formation, in a Patient with Adult-onset Steroid-refractory Henoch-Schönlein Purpura Nephritis

“…Moreover, by checking for a pathological improvement, we were able to reduce the dose of steroids without inducing recurrence of the nephritis. The following two mechanisms accounting for the improvement in cresent formation achieved with cyclophosphamide pulse therapy in this patient can be speculated: 1. the deposition of IgA in the mesangium was reduced by a decrease in the production of IgA as a result of suppression of the B cell activity caused by the therapy and 2. suppression of the fibroblast or myofibroblast activity by this therapy reduced the extent of fibrosis in the glomeruli (21,22). This is the first report of the use of cyclophosphamide pulse therapy to successfully improve both clinical symptoms and histopathological changes, such as crescent formation in the glomeruli, in a patient with HPSN.…”

Hypoxia Enhances the Senescence Effect of Bortezomib—The Proteasome Inhibitor—On Human Skin Fibroblasts

“…It is a common program that is activated by normal cells in response to various types of stress. It has been named “stress-induced premature senescence” [23]. This type of senescence can act as a tumour suppressor in order to prevent damaged cells to multiply as well as a secondary outcome for cancer cells due to therapeutic treatments [18].…”