Cidofovir administered with radiation displays an antiangiogenic effect mediated by E6 inhibition and subsequent TP53-dependent VEGF repression in HPV18+ cell lines.
Therapeutic administration of the antiviral agent cidofovir with radiation markedly enhanced the antitumor effect of ionizing radiation in cells of two HPV18+ human cervical carcinoma cell lines. Although this potent radiosensitizing effect was associated with repression of the viral oncoproteins E6/ E7 and restoration of TP53 as shown previously, additional mechanisms may be involved. In the present study, we investigated the antiangiogenic effect of the combination of cidofovir and radiation in cells of two HPV18+ cervical cancer cell lines, HeLa and ME180, and assessed the molecular mechanisms associated with the antiangiogenic effect observed. Cells were exposed to cidofovir (10 microg/ml) and irradiated (1-9 Gy). The angiogenic response was studied in vitro by a matrigel invasion assay. Modulations of E6, TP53 and VEGF mRNA and protein levels were studied by real-time RT-PCR, Western blot analysis and ELISA, respectively. Then a double RNA interference approach was used to analyze the connection between E6/TP53 and VEGF. The combination of cidofovir and radiation had a potent antiangiogenic effect. It induced E6 inhibition, restoration of TP53, and reduction of the proangiogenic phenotype of HPV18+ cells associated with VEGF inhibition. A siRNA strategy showed an anti-VEGF action of the combination mediated directly by E6 inhibition and TP53 restoration, since E6 siRNA inhibited VEGF whereas co-transfection with E6 and TP53 siRNA abrogated the anti-VEGF effect. This study showed that the combination of cidofovir with ionizing radiation has an antiangiogenic effect associated with VEGF inhibition subsequent to E6 inhibition and TP53 restoration.
Amine
Abdessamad
A
Laboratoire UPRES EA 27-10 Radiosensibilité des tumeurs et tissus sains, Institut Gustave Roussy, Villejuif, France.
Vozenin-Brotons
Marie-Catherine
MC
Abdulkarim
Bassam
B
Violot
Dominique
D
Aubel
Corinne
C
Bourhis
Jean
J
D042501:Angiogenic Proteins / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D006801:Humans; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D063065:Organophosphonates / Q000008:administration & dosage*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D042501:Angiogenic Proteins; D000970:Antineoplastic Agents; D063065:Organophosphonates; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D003596:Cytosine; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D000077404:Cidofovir