Document Detail

Apoptosis of squamous cells at different stages of carcinogenesis following 4-HPR treatment.
MedLine Citation:
PMID:  11895859     Owner:  NLM     Status:  MEDLINE    
Squamous cell carcinoma (SCC) is the end product of a multistep process characterized by a progression from normal epithelial cells through metaplastic or dysplastic intraepithelial changes that evolve into invasive cancer. Since retinamides have shown promising in vivo anti-tumoral activity, we studied effects and effector mechanisms of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) on squamous cells at progressing stages of tumorigenesis. To this end, an in vitro model of squamous carcinogenesis consisting of normal human keratinocytes, human papilloma virus (HPV)-immortalized keratinocytes (UP) and tumorigenic HPV-immortalized/v-Ha-ras transfected keratinocytes (UPR) was used. 4-HPR treatment affected cell growth at doses higher than 1.5 microM. Flow cytometric measurements of DNA content and annexin V revealed that cell growth decrease was mainly due to apoptosis at 4-HPR concentrations of or below 15 microM, and necrosis at higher concentrations. The effects were similar in the three cell types of the in vitro model, as well as in three SCC cell lines, suggesting that sensitivity to 4-HPR is independent of the degree of squamous cell tumorigenesis in the in vitro model. We further investigated whether mitochondrial damage was involved in the course of 4-HPR-induced apoptosis. Treatment of squamous cells with the antioxidant L-ascorbic acid inhibited apoptosis, indicating that 4-HPR increases production of free radicals. Measures of mitochondrial membrane potentials showed that 4-HPR induced membrane permeability transition (MPT), and that MPT-inhibitors were able to reduce apoptosis. This indicates that MPT is involved in apoptosis signalling by 4-HPR. Finally, we studied the role of caspases. We found that caspases 8, 9 and 3 participate in 4-HPR-mediated apoptosis of squamous cells, and that MPT is an upstream event that regulates caspase activity. Caspase 8 was activated independently of the Fas-Fas ligand pathway.
Silvia Bruno; Claudya Tenca; Daniele Saverino; Ermanno Ciccone; Carlo E Grossi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Carcinogenesis     Volume:  23     ISSN:  0143-3334     ISO Abbreviation:  Carcinogenesis     Publication Date:  2002 Mar 
Date Detail:
Created Date:  2002-03-15     Completed Date:  2002-05-08     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  England    
Other Details:
Languages:  eng     Pagination:  447-56     Citation Subset:  IM    
Section of Human Anatomy, Department of Experimental Medicine, University of Genoa, Via De Toni 14, 16132 Genoa, Italy.
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MeSH Terms
Antigens, CD95 / metabolism
Antineoplastic Agents / pharmacology
Apoptosis / drug effects*
Caspases / metabolism
Cell Division / drug effects
Cell Line
Fas Ligand Protein
Fenretinide / pharmacology*
Flow Cytometry
Keratinocytes / cytology,  drug effects,  pathology
Membrane Glycoproteins / metabolism
Mitochondria / drug effects,  metabolism
Neoplasms, Squamous Cell / pathology*
Time Factors
Tumor Cells, Cultured
Reg. No./Substance:
0/Antigens, CD95; 0/Antineoplastic Agents; 0/FASLG protein, human; 0/Fas Ligand Protein; 0/Membrane Glycoproteins; 65646-68-6/Fenretinide; EC 3.4.22.-/Caspases

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