Document Detail


Dose- and time-dependent effects of doxorubicin on cytotoxicity, cell cycle and apoptotic cell death in human colon cancer cells.
MedLine Citation:
PMID:  20346999     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The cytostatic drug doxorubicin is a well-known chemotherapeutic agent which is used in treatment of a wide variety of cancers. A key factor in the response of cancer cells to chemotherapeutic drugs is the activation of the apoptotic pathway, a pathway that is often impaired in chemoresistant colon cancer cells. The aim of the present study was to investigate the effects of doxorubicin in Hct-116 human colon carcinoma cells in order to clarify if a time/concentration range for optimal doxorubicin-induced apoptosis exists. We compared a treatment schedule were cells were bolus incubated for 3h with doxorubicin followed by 24h in drug-free medium, with a continuous doxorubicin treatment schedule for 24h. Bolus incubation was carried out to determine effects of doxorubicin accumulated during the first 3h, whereas continuous incubation allowed further (continuous) exposure to doxorubicin. We found that bolus (3h) treatment with doxorubicin resulted in a dose-dependent decrease of viable cells and concomitant increase of apoptosis. Additionally, bolus (3h) doxorubicin incubation led to phosphorylation of p53 at serine 392, induction of p21, G2 arrest and increase of proapoptotic protein Bax. In contrast, continuous (24h) treatment with doxorubicin reduced the number of living cells with no parallel raise in the amount of dead cells. Continuous (24h) treatment with 5 microM doxorubicin resulted in cell cycle arrest in G0/G1 phase that was neither accompanied by phosphorylation and activation of p53 nor enhanced expression of p21. These results suggest that doxorubicin is able to induce cell death by apoptosis only at particular dose and treatment conditions and imply a completely different cellular response following bolus or continuous exposure to doxorubicin.
Authors:
Regine L?pertz; Wim W?tjen; Regine Kahl; Yvonni Chovolou
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Publication Detail:
Type:  Journal Article     Date:  2010-03-25
Journal Detail:
Title:  Toxicology     Volume:  271     ISSN:  1879-3185     ISO Abbreviation:  Toxicology     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-10     Completed Date:  2010-05-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0361055     Medline TA:  Toxicology     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  115-21     Citation Subset:  IM    
Affiliation:
Institute of Toxicology, Heinrich Heine University of Duesseldorf, P.O. Box 10 10 07, D-40001 D?sseldorf, Germany.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Cell Cycle / drug effects*
Cell Death / drug effects
Colonic Neoplasms / pathology*
Doxorubicin / pharmacology*
G1 Phase / drug effects
HCT116 Cells
Humans
Tumor Suppressor Protein p53 / metabolism
bcl-2-Associated X Protein / metabolism
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Tumor Suppressor Protein p53; 0/bcl-2-Associated X Protein; 23214-92-8/Doxorubicin

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