Abstract
Often the use of cytotoxic drugs in cancer therapy results in stable disease rather than regression of the tumor, and this is typically seen as a failure of treatment. We now show that DNA damage is able to induce senescence in tumor cells expressing wild-type p53. We also show that cytotoxics are capable of inducing senescence in tumor tissue in vivo. Our results suggest that p53 and p21 play a central role in the onset of senescence, whereas p16(INK4a) function may be involved in maintaining senescence. Thus, like apoptosis, senescence appears to be a p53-induced cellular response to DNA damage and an important factor in determining treatment outcome.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Camptothecin / analogs & derivatives
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Camptothecin / pharmacology
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Cell Cycle / drug effects
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Cellular Senescence / drug effects
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Cellular Senescence / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / biosynthesis
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DNA Damage / physiology*
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Etoposide / pharmacology
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Humans
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Irinotecan
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Neoadjuvant Therapy
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Tumor Suppressor Protein p53 / biosynthesis
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Tumor Suppressor Protein p53 / physiology
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beta-Galactosidase / metabolism
Substances
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Antineoplastic Agents, Phytogenic
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Tumor Suppressor Protein p53
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Etoposide
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Irinotecan
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beta-Galactosidase
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Camptothecin