Document Detail


Cross-talk between DNA damage and cell survival checkpoints during G2 and mitosis: pharmacologic implications.
MedLine Citation:
PMID:  16373717     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this study, we wanted to clarify the role of survivin-mediated survival signaling during G2 and M in tumor cells treated with DNA-damaging agents. As a cellular model, we selected MOLT-4 human T-cell lymphoblastic leukemia cells that overexpress survivin and nonfunctional p53. Treatment with melphalan, a classic DNA-damaging agent, led to the induction of the DNA damage checkpoint and growth arrest in the G2 phase of the cell cycle. Checkpoint abrogation by caffeine was accompanied by mitotic entry and rapid apoptotic cell death, whereas cells remaining in G2 remained viable during the same time interval. Unexpectedly, when the spindle checkpoint was activated following G2 abrogation, two different effects could be observed. If the microtubules of the melphalan-treated cells were destabilized by nocodazole, cells became arrested in prometaphase with low survivin levels and entered apoptosis. In contrast, if the microtubules of the melphalan-treated cells were stabilized by taxol, cells were still arrested in prometaphase, but apoptotic execution was inhibited. This effect is, most likely, directly mediated by survivin itself given its well-established antiapoptotic functions. In conclusion, depending on the way the spindle checkpoint was activated in cells with damaged DNA, cells could be either protected by survivin or die during mitosis. We suggest that the efficacy of DNA damage checkpoint abrogators used in combination with DNA-damaging agents may critically depend on whether DNA damage is able to invoke spindle checkpoint response and to activate survivin-associated survival signaling during mitosis.
Authors:
Przemyslaw Bozko; Michal Sabisz; Annette K Larsen; Andrzej Skladanowski
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  4     ISSN:  1535-7163     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2005 Dec 
Date Detail:
Created Date:  2005-12-23     Completed Date:  2006-03-02     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2016-25     Citation Subset:  IM    
Affiliation:
Laboratory of Molecular and Cellular Pharmacology, Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Narutowicza Street 11/12, 80-952 Gdansk, Poland.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Alkylating / pharmacology
Blotting, Western
Caffeine / pharmacology
Cell Line
Cell Survival*
DNA Damage*
DNA Fragmentation
G2 Phase / drug effects*
Humans
Melphalan / pharmacology
Mitosis / drug effects*
Nocodazole / pharmacology
Paclitaxel / pharmacology
Signal Transduction
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 148-82-3/Melphalan; 31430-18-9/Nocodazole; 33069-62-4/Paclitaxel; 58-08-2/Caffeine

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