A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents

Exposure of human tumor cell lines to different chemotherapeutic drugs, ionizing radiation, and differentiating agents induced morphological, enzymatic, and ploidy changes resembling replicative senescence of normal cells. Moderate doses of doxorubicin induced this senescence-like phenotype (SLP) in...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1999-08, Vol.59 (15), p.3761-3767
Main Authors: CHANG, B.-D, BROUDE, E. V, DOKMANOVIC, M, HONGMING ZHU, RUTH, A, YONGZHI XUAN, KANDEL, E. S, LAUSCH, E, CHRISTOV, K, RONINSON, I. B
Format: Article
Language:English
Subjects:
Adenocarcinoma - pathology
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Antineoplastic Agents, Phytogenic - pharmacology
Biological and medical sciences
Breast Neoplasms - pathology
Cell Division - drug effects
Cellular Senescence - drug effects
Chemotherapy
Doxorubicin - pharmacology
Female
Fibrosarcoma - pathology
Gamma Rays
Humans
Medical sciences
Mice
Mice, Nude
Neoplasm Transplantation
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - pathology
Neoplastic Stem Cells - radiation effects
Pharmacology. Drug treatments
Phenotype
Ploidies
Tretinoin - pharmacology
Tumor Cells, Cultured - drug effects
Tumor Cells, Cultured - pathology
Tumor Cells, Cultured - radiation effects
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Summary:Exposure of human tumor cell lines to different chemotherapeutic drugs, ionizing radiation, and differentiating agents induced morphological, enzymatic, and ploidy changes resembling replicative senescence of normal cells. Moderate doses of doxorubicin induced this senescence-like phenotype (SLP) in 11 of 14 tested cell lines derived from different types of human solid tumors, including all of the lines with wild-type p53 and half of p53-mutated cell lines. SLP induction seemed to be independent from mitotic cell death, the other major effect of drug treatment. Among cells that survived drug exposure, SLP markers distinguished those cells that became terminally growth-arrested within a small number of cell divisions from the cells that recovered and resumed proliferation. SLP induction in breast carcinoma cells treated with retinoids in vitro or in vivo was found to correlate with permanent growth inhibition under the conditions of minimal cytotoxicity, suggesting that this response may be particularly important for the antiproliferative effect of differentiating agents. The senescence-like program of terminal proliferation arrest may provide an important determinant of treatment outcome and a target for augmentation in cancer therapy.
ISSN:0008-5472
1538-7445