| Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression. | |
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MedLine Citation:
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PMID: 20736003 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Approaches to overcome chemoresistance in cancer cells have involved targeting specific signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway, a stress response pathway known to be involved in the regulation of cell survival, apoptosis and growth. The present study determined the effect of PI3K inhibition on the clonogenic survival of human cancer cells following exposure to various chemotherapeutic agents. Treatment with the PI3K inhibitors LY294002 or Compound 15e resulted in increased survival of MDA-MB-231 breast carcinoma cells after exposure to doxorubicin, etoposide, 5-fluorouracil, and vincristine. Increased survival following PI3K inhibition was also observed in DU-145 prostate, HCT-116 colon and A-549 lung carcinoma cell lines exposed to doxorubicin. Increased cell survival mediated by LY294002 was correlated with a decrease in cell proliferation, which was linked to an increase in the proportion of cells in the G(1) phase of the cell cycle. Inhibition of PI3K signaling also resulted in higher levels of the cyclin-dependent kinase inhibitors p21(Waf1/Cip1) and p27(Kip1); and knockdown of p27(kip1) with siRNA attenuated resistance to doxorubicin in cells treated with LY294002. Incubation in the presence of LY294002 after exposure to doxorubicin resulted in decreased cell survival. These findings provide evidence that PI3K inhibition leads to chemoresistance in human cancer cells by causing a delay in cell cycle; however, the timing of PI3K inhibition (either before or after exposure to anti-cancer agents) may be a critical determinant of chemosensitivity. |
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Authors:
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Gail T McDonald; Richard Sullivan; Geneviève C Paré; Charles H Graham |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-22 |
Journal Detail:
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Title: Experimental cell research Volume: 316 ISSN: 1090-2422 ISO Abbreviation: Exp. Cell Res. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-25 Completed Date: 2010-11-10 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0373226 Medline TA: Exp Cell Res Country: United States |
Other Details:
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Languages: eng Pagination: 3197-206 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada K7L 3N6. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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1-Phosphatidylinositol 3-Kinase
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antagonists & inhibitors*,
metabolism Antineoplastic Agents / pharmacology* Apoptosis / drug effects Cell Cycle / drug effects* Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Chromones / pharmacology Clone Cells Cyclin-Dependent Kinase Inhibitor p27 / metabolism Doxorubicin / pharmacology Drug Resistance, Neoplasm / drug effects* Flow Cytometry Gene Knockdown Techniques Humans Morpholines / pharmacology Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-akt / metabolism RNA, Small Interfering / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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MOP-57871//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Chromones; 0/Morpholines; 0/Protein Kinase Inhibitors; 0/RNA, Small Interfering; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 23214-92-8/Doxorubicin; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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