Abstract | PURPOSE: Premature or stress-induced senescence is a major cellular response to chemotherapy in solid tumors and contributes to successful treatment. However, senescent tumor cells are resistant to apoptosis and may also reenter the cell cycle. We set out to find a means to specifically induce senescent tumor cells to undergo cell death and not to reenter the cell cycle that may have general application in cancer therapy. EXPERIMENTAL DESIGN: We investigated the mechanisms regulating cell survival in drug-induced senescent tumor cells. Using immunofluorescence and flow cytometry-based techniques, we established the status of the ataxia telangiectasia mutated (ATM) signaling pathway in these cells. We assayed the requirement of ATM signaling and p21(CIP1) expression for survival in premature senescent tumor cells using pharmacologic inhibitors and antisense oligonucleotides. RESULTS: The ATM/ATR (ATM- and Rad3-related) signaling pathway was found to be constitutively active in drug-induced senescent tumor cells. We found that blocking ATM/ATR signaling with pharmacologic inhibitors, including the novel ATM inhibitors KU55933 and CGK733, induced senescent breast, lung, and colon carcinoma cells to undergo cell death. We show that the mechanism of action of this effect is directly via p21(CIP1), which acts downstream of ATM. This is in contrast to the effects of ATM inhibitors on normal, untransformed senescent cells. CONCLUSIONS: Blocking ATM and/or p21(CIP1) following initial treatment with a low dose of senescence-inducing chemotherapy is a potentially less toxic and highly specific treatment for carcinomas.
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Authors | Elvira Crescenzi, Giuseppe Palumbo, Jasper de Boer, Hugh J M Brady |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 14
Issue 6
Pg. 1877-87
(Mar 15 2008)
ISSN: 1078-0432 [Print] United States |
PMID | 18347191
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
- Benzeneacetamides
- CDKN1A protein, human
- CGK 733
- Cell Cycle Proteins
- Cyclin-Dependent Kinase Inhibitor p21
- DNA-Binding Proteins
- Morpholines
- Pyrones
- Tumor Suppressor Proteins
- ATM protein, human
- Ataxia Telangiectasia Mutated Proteins
- Protein Serine-Threonine Kinases
- Thiourea
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Topics |
- Ataxia Telangiectasia Mutated Proteins
- Benzeneacetamides
(pharmacology)
- Breast Neoplasms
(drug therapy, physiopathology)
- Carcinoma
(drug therapy, physiopathology)
- Cell Cycle
(drug effects)
- Cell Cycle Proteins
(antagonists & inhibitors, physiology)
- Cell Survival
(drug effects)
- Cellular Senescence
(drug effects, physiology)
- Colonic Neoplasms
(drug therapy, physiopathology)
- Cyclin-Dependent Kinase Inhibitor p21
(genetics, physiology)
- DNA Damage
(drug effects)
- DNA-Binding Proteins
(antagonists & inhibitors, physiology)
- Drug Evaluation, Preclinical
- Gene Expression Regulation, Neoplastic
(drug effects)
- HCT116 Cells
- Humans
- Lung Neoplasms
(drug therapy, physiopathology)
- Morpholines
(pharmacology)
- Protein Serine-Threonine Kinases
(antagonists & inhibitors, physiology)
- Pyrones
(pharmacology)
- Thiourea
(analogs & derivatives, pharmacology)
- Tumor Cells, Cultured
- Tumor Suppressor Proteins
(antagonists & inhibitors, physiology)
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