Document Detail

Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy.
MedLine Citation:
PMID:  20436269     Owner:  NLM     Status:  MEDLINE    
The effects of inhibition of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways and chemotherapeutic drugs on cell cycle progression and drug sensitivity were examined in cytokine-dependent FL5.12 hematopoietic cells. We examined their effects, as these cells resemble normal hematopoietic precursor cells as they do not exhibit "oncogene-addicted" growth, while they do display "cytokine-addicted" proliferation as cytokine removal resulted in apoptosis in greater than 80% of the cells within 48 hrs. When cytokine-dependent FL5.12 cells were cultured in the presence of IL-3, which stimulated multiple proliferation and anti-apoptotic cascades, MEK, PI3K and mTOR inhibitors transiently suppressed but did not totally inhibit cell cycle progression or induce apoptosis while chemotherapeutic drugs such as doxorubicin and paclitaxel were more effective in inducing cell cycle arrest and apoptosis. Doxorubicin induced a G(1) block, while paclitaxel triggered a G(2)/M block. Doxorubicin was more effective in inducing cell death than paclitaxel. Furthermore the effects of doxorubicin could be enhanced by addition of MEK, PI3K or mTOR inhibitors. Cytokine-dependent cells which proliferate in vitro and are not "oncogene-addicted" may represent a pre-malignant stage, more refractory to treatment with targeted therapy. However, these cells are sensitive to chemotherapeutic drugs. It is important to develop methods to inhibit the growth of such cytokine-dependent cells as they may resemble the leukemia stem cell and other cancer initiating cells. These results demonstrate the enhanced effectiveness of targeting early hematopoietic progenitor cells with combinations of chemotherapeutic drugs and signal transduction inhibitors.
Stephen L Abrams; Linda S Steelman; John G Shelton; William Chappell; Jörg Bäsecke; Franca Stivala; Marco Donia; Ferdinando Nicoletti; Massimo Libra; Alberto M Martelli; James A McCubrey
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-05-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  9     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-31     Completed Date:  2010-09-03     Revised Date:  2013-10-23    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1839-46     Citation Subset:  IM    
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
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MeSH Terms
Antibiotics, Antineoplastic / therapeutic use
Antineoplastic Agents / therapeutic use*
Butadienes / therapeutic use
Cell Line, Tumor
Chromones / therapeutic use
Doxorubicin / therapeutic use
G1 Phase
Interleukin-3 / therapeutic use
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*,  metabolism
Leukemia, Prolymphocytic / drug therapy
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*,  metabolism
Morpholines / therapeutic use
Nitriles / therapeutic use
Paclitaxel / therapeutic use
Phosphatidylinositol 3-Kinases / antagonists & inhibitors*,  metabolism
Protein-Serine-Threonine Kinases / antagonists & inhibitors*,  metabolism
Signal Transduction / drug effects*
Sirolimus / therapeutic use
TOR Serine-Threonine Kinases
Grant Support
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Antineoplastic Agents; 0/Butadienes; 0/Chromones; 0/Interleukin-3; 0/Intracellular Signaling Peptides and Proteins; 0/Morpholines; 0/Nitriles; 0/U 0126; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 23214-92-8/Doxorubicin; 33069-62-4/Paclitaxel; 53123-88-9/Sirolimus; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Serine-Threonine Kinases; EC protein, mouse; EC Kinases; EC Protein Kinase Kinases

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