Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

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

Oncogene volume 21, pages 2334–2346 (2002)Cite this article

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 p21WAF1/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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Abdulkarim B, Bourhis J . 2001 Lancet Oncology 2: 622–630

  • Andrei G, Snoeck R, Piette J, Delvenne P, De Clercq E . 1998 Oncol. Res. 10: 523–531

  • Alvaraz-Salas LM, Cullinan AE, Siwkowski A, Hampel A, DiaPaolo A . 1998 Proc. Natl. Acad. Sci. USA 95: 1189–1194

  • Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumuro K, Mizutani S . 1999 EMBO. J. 18: 1223–1234

  • Bartek J, Bartkova J, Lukas J . 1997 Exp. Cell. Res. 237: 1–6

  • Berezutskaya E, Yu B, Morozov A, Raychaudhuri P, Bagchi S . 1997 Cell Growth Differ. 8: 1277–1286

  • Boyer SN, Wazer DE, Band V . 1996 Cancer Res. 56: 4620–4624

  • Butz K, Denk C, Ullmann A, Scheffner M, Hoppe-Seyler F . 2000 Proc. Natl. Acad. Sci. USA 6: 6693–6697

  • Butz K, Shahabeddin L, Geisen C, Spitkovsky D, Ullmann A, Hoppe-Seyler F . 1995 Oncogene 10: 927–936

  • Cai Z, Capoulade C, Moyret-Lalle C, Amor-Gueret M, Feunteun J, Larsen AK, Paillerets BB, Chouaib S . 1997 Oncogene 15: 2817–2826

  • Chew YP, Ellis M, Wilkie S, Mittnacht S . 1998 Oncogene 29: 2177–2186

  • Chiba I, Shindoh M, Yasuda M, Yamazaki Y, Amemiya A, Sato Y, Fujinaga K, Notani K, Fukuda H . 1996 Oncogene 12: 1663–1668

  • Crook T, Parker GA, Rozycka M, Crossland S, Allday MJ . 1998 Oncogene 16: 1429–1441

  • Demers GW, Espling E, Harry JB, Etscheid BG, Galloway A . 1996 J. Virol. 70: 6862–6869

  • DiPaolo JA, Popescu NC, Alvarez L, Woodworth CD . 1993 Crit. Rev. Oncog. 4: 337–3360

  • El-Deiry WS, Tokino T, Valculescu VE, Levy DB, Parsons R, Trent JM, Lind D, Mercer WE, Kinzler KW, Vogelstein B . 1993 Cell 75: 817–825

  • Flaman JM, Frebourg T, Moreau V, Charbonnier F, Martin C, Chappuis P, Sappino AP, Limacher IM, Bron L, Benhattar J . 1995 Proc. Natl. Acad. Sci. USA 92: 3963–3967

  • Francis DA, Schmid SI, Howley PM . 2000 J. Virol. 74: 2679–2686

  • Freedman DA, Levine AJ . 1998 Mol. Cell. Biol. 18: 7288–7293

  • Funk JO, Waga S, Harry JB, Espling E, Stillman B, Galloway DA . 1997 Genes Dev. 11: 2090–2100

  • Gallardo D, Drazan K, McBride W . 1996 Cancer Res. 56: 4891–4903

  • Gillison ML, Koch WM, Shah KV . 1999 Curr. Opin. Oncol. 11: 1–9

  • Goodwin EC, DiMaio D . 2000 Proc. Natl. Acad. Sci. USA 97: 12513–12518

  • Goodwin EC, Yang E, Lee CJ, Lee HW, DiMaio D, Hwang ES . 2000 Proc. Natl. Acad. Sci. USA 97: 10978–10983

  • Goubin F, Ducommun B . 1995 Oncogene 10: 2281–2287

  • He Y, Huang L . 1997 Cancer Res. 57: 3993–3993

  • Hengstermann A, Linares LK, Ciechanover A, Whitaker NJ, Scheffner M . 2001 Proc. Natl. Acad. Sci. USA 98: 1218–1223

  • Hickman ES, Picksley SM, Vousden KH . 1994 Oncogene 9: 2177–2181

  • Hietanen S, Lain S, Krausz E, Blattner C, Lane DP . 2000 Proc. Natl. Acad. Sci. USA 97: 8501–8506

  • Hu G, Liu W, Hanania EG, Fu S, Wang T, Deisseroth AB . 1995 Cancer. Gene. Ther. 2: 19–32

  • Hwang ES, Naeger LK, DiMaio D . 1996 Oncogene 15: 795–803

  • Jeon S, Allen-Hoffmann BI, Lambert PF . 1995 J. Virol. 69: 2989–2997

  • Johnson JA, Gangemi JD . 2000 Antimicrob. Agents. Chemother. 43: 198–205

  • Jones DL, Alani RM, Munger K . 1997a Genes Dev. 11: 2101–2111

  • Jones DL, Thompson DA, Munger K . 1997b Virology 239: 97–107

  • Kaelin Jr WG . 1999 Bioessays 21: 950–958

  • Kamradt MC, Mohideen N, Krueger E, Walter S, Vaughan AT . 2000 Br. J. Cancer 82: 1709–1716

  • Knudsen ES, Buckmaster C, Chen TT, Feramisco JR, Wang JY . 1998 Genes Dev. 12: 2278–2292

  • Knudsen KE, Fribourg AF, Strobeck MW, Blanchard JM, Knudsen ES . 1999 J. Biol. Chem. 274: 27632–27641

  • Knudsen KE, Booth D, Naderi S, Sever-Chroneos Z, Fribourg AF, Hunton IC, Feramisco JR, Wang JY, Knudsen ES . 2000 Mol. Cell. Biol. 20: 7751–7763

  • Lazo PA . 1999 Br. J. Cancer 80: 2008–2018

  • Levine AJ . 1997 Cell 88: 323–331

  • Liekens S, Verbeken E, De Clercq E, Neyts N . 2001 Int. J. Cancer 92: 161–167

  • Mantovani F, Banks L . 1999 Oncogene 18: 3309–3315

  • Moran E . 1993 Curr. Opin. Genet. Dev. 13: 261–291

  • Neyts J, Sadler R, De Clercq E, Raab-Traub N, Pagano JS . 1998 Cancer Res. 58: 384–388

  • Pisarev VM, Lee SH, Connelly MC, Fridland A . 1997 Mol. Pharmacol. 52: 63–68

  • Safrin S, Cherrigton J, Jaffe HS . 1997 Rev. Med. Virol. 7: 145–156

  • Santin AD, Hermonat PL, Ravaggi A, Chiriva-Internati M, Pecorelli S, Parham GP . 1998 Cancer 83: 2346–2352

  • Scheffner M, Munger K, Byrne JC, Howley PM . 2000 Proc. Natl. Acad. Sci. USA 88: 5523–5527

  • Scheffner M, Huibregtse JM, Vierstra RD, Howley PM . 1993 Cell 75: 495–505

  • Schiffman MH . 1995 J. Nat. Can. Inst. 87: 1345–1347

  • Slebos RJ, Lee MH, Plunkett BS, Kessis TD, Williams BO, Jacks T, Hedrick L, Kastan MB, Cho KR . 1994 Proc. Natl. Acad. Sci. USA 91: 5320–5324

  • Smith-McCune K, Kalman D, Robbins C, Shivakumar S, Yuschenkoff L, Bishop JM . 1999 Proc. Natl. Acad. Sci. USA 96: 6999–7004

  • Spitz FR, Nguyen D, Skibbe JM, Meyn RE, Cristiano RJ, Roth JA . 1996 Clin. Cancer Res. 2: 1665–1671

  • Steele C, Cowsert LM, Shillitoe EJ . 1993 Cancer Res. 15: 2330–2337

  • Steele C, Sacks PG, Adler-Storthz K, Shillitoe EJ . 1992 Cancer Res. 52: 4706–4711

  • Stoppler H, Stoppler MC, Johnson E et al . 1998 Oncogene 17: 1207–1214

  • Tan TM, Ting RC . 1995 Cancer Res. 55: 4599–4605

  • Venturini F, Braspenning J, Homann M, Gissmann L, Sczakiel G . 1999 Nucleic Acids Res. 27: 1585–1592

  • Villa LL . 1997 Adv. Cancer Res. 71: 321–341

  • von Knebel-Doeberitz M, Oltersdorf T, Schwarz E, Gissmann L . 1988 Cancer Res. 48: 3780–3786

  • Wu L, Goodwin EC, Naeger LK, Vigo E, Galaktionov K, Helin K, DiMaio D . 2000 Mol. Cell 20: 7059–7067

  • zur Hausen H . 2000 J. Natl. Cancer Inst. 92: 690–698

Download references

Acknowledgements

We are especially grateful to Dr S Chouaïb for his constructive discussion about the experiments and for the critical reading of the manuscript.

Author information

Author notes

  1. Bassam Abdulkarim and Siham Sabri: B Abdulkarim and S Sabri contributed equally to the work

Authors and Affiliations

  1. Laboratoire UPRES EA N°27-10 ‘Radiosensibilité-Radiocarcinogénèse humaine’ and Unité METSI, Institut Gustave-Roussy, Villejuif, 94805, France

    Bassam Abdulkarim, Eric Deutsch, Laurence Maggiorella, François Eschwege & Jean Bourhis

  2. INSERM U362, Institut Gustave-Roussy, Villejuif, 94805, France

    Siham Sabri, Heddia Chagraoui & William Vainchenker

  3. INSERM U487 Cytokines et immunologie des tumeurs humaines, Institut Gustave-Roussy, Villejuif, 94805, France

    Jerome Thierry & Salem Chouaïb

Authors
  1. Bassam Abdulkarim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Siham Sabri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric Deutsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heddia Chagraoui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laurence Maggiorella
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jerome Thierry
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. François Eschwege
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. William Vainchenker
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Salem Chouaïb
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean Bourhis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean Bourhis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abdulkarim, B., Sabri, S., Deutsch, E. et al. Antiviral agent Cidofovir restores p53 function and enhances the radiosensitivity in HPV-associated cancers. Oncogene 21, 2334–2346 (2002). https://doi.org/10.1038/sj.onc.1205006

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205006

Keywords

This article is cited by

Search

Advanced search

Quick links