Antiviral agent Cidofovir restores p53 function and enhances the radiosensitivity in HPV-associated cancers.
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.
Abdulkarim
Bassam
B
Laboratoire UPRES EA N degrees 27-10 'Radiosensibilité-Radiocarcinogénèse humaine' and Unité METSI, Institut Gustave-Roussy, 94805 Villejuif, France.
Sabri
Siham
S
Deutsch
Eric
E
Chagraoui
Heddia
H
Maggiorella
Laurence
L
Thierry
Jerome
J
Eschwege
François
F
Vainchenker
William
W
Chouaïb
Salem
S
Bourhis
Jean
J
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D000077404:Cidofovir; D019925:Cyclin A / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000628:therapy / Q000821:virology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D027383:Papillomaviridae / Q000378:metabolism; D030361:Papillomavirus Infections / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D014412:Tumor Virus Infections / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000628:therapy / Q000821:virology; D023041:Xenograft Model Antitumor Assays
D000998:Antiviral Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009856:Oncogene Proteins, Viral; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011838:Radiation-Sensitizing Agents; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D003596:Cytosine; D000077404:Cidofovir