Document Detail

Regulation of G1/S transition and induction of apoptosis in HL-60 leukemia cells by fenretinide (4HPR).
MedLine Citation:
PMID:  9724094     Owner:  NLM     Status:  MEDLINE    
We previously reported that all-trans retinoic acid (RA) and fenretinide (4HPR) suppress HL-60 leukemia cell growth and cause partial cell arrest in the G1-to-S phase. Moreover, 4HPR but not RA induces apoptosis in HL-60 cells. To investigate further the observed biological effects, cyclin D1 and cdk4 expression and the level of phosphorylation of the retinoblastoma protein Rb were assessed. Cyclin D1 and cdk4 expression and Rb phosphorylation were significantly reduced, by 40-75%, after 24 hr of treatment with RA or 4HPR; these decreases were either transient, e.g., only at 24 hr for cdk4, or sustained for 72 hr. In general, more pronounced decreases were seen in the 4HPR-treated cells. Evidence for 4HPR-induced apoptosis comes from (1) cleavage of the enzyme poly(ADP-ribose) polymerase (PARP) to an 89-kDa truncated product, (2) appearance of DNA ladders on agarose gel electrophoresis, and (3) higher incorporation in situ of digoxigenin nucleotides into the free 3'-ends of DNA. Overnight pretreatment with 0.5-5.0 microM of the CPP32 inhibitor DEVD, but not the ICE inhibitor YVAD, significantly reduced the specific processing of PARP, suggesting that CPP32 is involved in the mechanism of action of 4HPR. Analysis of 2 lipid-derived second messengers, ceramide and diacylglycerol (DAG), as a function of time of treatment with RA or 4HPR, showed ceramide but not DAG to be significantly albeit transiently increased 2-fold at 3 hr, by 4HPR. To test further whether ceramide may be involved in the signaling cascade that culminates in the induction of apoptosis in 4HPR-treated HL-60 cells, the effects of fumonisin B1, an inhibitor of ceramide synthase, were studied. Simultaneous treatment of cells with 4HPR and 25-100 microM fumonisin B1 resulted in a dose-dependent reduction in the elevation in ceramide, the extent of PARP cleavage, and induction of apoptosis. Pretreatment with DEVD or YVAD, on the other hand, had no effect on the 4HPR-induced increase in ceramide.
A M DiPietrantonio; T C Hsieh; S C Olson; J M Wu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  78     ISSN:  0020-7136     ISO Abbreviation:  Int. J. Cancer     Publication Date:  1998 Sep 
Date Detail:
Created Date:  1998-09-08     Completed Date:  1998-09-08     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  53-61     Citation Subset:  IM    
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla 10595, USA.
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MeSH Terms
Anticarcinogenic Agents / pharmacology*
Apoptosis* / genetics
Carboxylic Acids / pharmacology
Carcinogens, Environmental / pharmacology
Ceramides / metabolism
Cyclin D1 / metabolism
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinases / metabolism
DNA Fragmentation
DNA, Neoplasm / analysis
Diglycerides / metabolism
Fenretinide / pharmacology*
G1 Phase / drug effects*
HL-60 Cells / drug effects*,  physiology
Proto-Oncogene Proteins*
Retinoblastoma Protein / metabolism
S Phase / drug effects*
Time Factors
Reg. No./Substance:
0/Anticarcinogenic Agents; 0/Carboxylic Acids; 0/Carcinogens, Environmental; 0/Ceramides; 0/DNA, Neoplasm; 0/Diglycerides; 0/Fumonisins; 0/Proto-Oncogene Proteins; 0/Retinoblastoma Protein; 116355-83-0/fumonisin B1; 136601-57-5/Cyclin D1; 65646-68-6/Fenretinide; EC protein, human; EC Kinase 4; EC Kinases

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