Antiviral agent Cidofovir restores p53 function and enhances the radiosensitivity in HPV-associated cancers.

Details

Serval ID
serval:BIB_D37A37101F7D
Type
Article: article from journal or magazin.
Collection
Publications
Title
Antiviral agent Cidofovir restores p53 function and enhances the radiosensitivity in HPV-associated cancers.
Journal
Oncogene
Author(s)
Abdulkarim B., Sabri S., Deutsch E., Chagraoui H., Maggiorella L., Thierry J., Eschwege F., Vainchenker W., Chouaïb S., Bourhis J.
ISSN
0950-9232 (Print)
ISSN-L
0950-9232
Publication state
Published
Issued date
2002
Peer-reviewed
Oui
Volume
21
Number
15
Pages
2334-2346
Language
english
Notes
Publication types: Journal Article Publication Status: ppublish
Abstract
High-risk human papillomaviruses (HPVs) have been associated to the development of cervical and some other human cancers. Most of them express E6 and E7 oncoproteins, able to bind to p53 and retinoblastoma (pRb) tumor suppressor proteins respectively and neutralize their function. Restoration of these pathways by blocking E6 and E7 expression would provide a selective therapeutic effect. Here, we show that a clinically approved antiviral agent Cidofovir reduced E6 and E7 expression in cervical carcinoma Me180 and head and neck squamous cell carcinoma HEP2 cells at the transcriptional level. Cidofovir induced the accumulation of active p53 and pRb associated to induction of cyclin dependent kinase inhibitor p21(WAF1/CIP1) in Me180 and HEP2 cells. p53 induction was also shown in Hela HPV-positive cervical carcinoma cell line. In addition, S phase cell cycle accumulation with concomitant decrease of cyclin A expression were associated to the antiproliferative activity of Cidofovir in HPV-treated cells. Combining Cidofovir to irradiation both in vivo and in nude mice xenografts resulted in a marked radiosensitization in HPV-positive cells, which was not observed in virus negative cells. This study provides the basis for a new anticancer strategy to enhance the antitumor effect of ionizing radiation in HPV-related cancers, without increase deleterious effects.
Keywords
Animals, Antiviral Agents/pharmacology, Carcinoma/metabolism, Carcinoma/therapy, Cell Division/drug effects, Cell Division/radiation effects, Cyclin A/metabolism, Cyclin-Dependent Kinase Inhibitor p21, Cyclins/biosynthesis, Cytosine/analogs & derivatives, Cytosine/pharmacology, Female, Head and Neck Neoplasms/metabolism, Head and Neck Neoplasms/therapy, Humans, Mice, Mice, Nude, Oncogene Proteins, Viral/metabolism, Organophosphonates, Organophosphorus Compounds/pharmacology, Papillomaviridae/metabolism, Papillomavirus Infections/metabolism, Papillomavirus Infections/therapy, Radiation, Ionizing, Radiation-Sensitizing Agents/pharmacology, Retinoblastoma Protein/metabolism, Tumor Cells, Cultured, Tumor Suppressor Protein p53/physiology, Tumor Virus Infections/metabolism, Tumor Virus Infections/therapy, Uterine Cervical Neoplasms/metabolism, Uterine Cervical Neoplasms/therapy, Xenograft Model Antitumor Assays
Pubmed
Web of science
Open Access
Yes
Create date
01/12/2014 18:00
Last modification date
20/08/2019 15:53
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