This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Abou El Hassan, M. A. I.
Right arrow Articles by Kruyt, F. A. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Abou El Hassan, M. A. I.
Right arrow Articles by Kruyt, F. A. E.

 Previous Article  |  Next Article 

Journal of Virology, November 2004, p. 12243-12251, Vol. 78, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.22.12243-12251.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Conditionally Replicating Adenoviruses Kill Tumor Cells via a Basic Apoptotic Machinery-Independent Mechanism That Resembles Necrosis-Like Programmed Cell Death

Mohamed A. I. Abou El Hassan, Ida van der Meulen-Muileman, Saman Abbas, and Frank A. E. Kruyt*

Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

Received 15 April 2004/ Accepted 1 July 2004

Conditionally replicating adenoviruses (CRAds) represent a promising class of novel anticancer agents that are used for virotherapy. The E1A{Delta}24 mutation-based viruses, Ad5-{Delta}24 [CRAd(E3–); E3 region deleted] and infectivity-enhanced Ad5-{Delta}24RGD [CRAd(E3+)] have been shown to potently eradicate tumor cells. The presence of the E3 region in the latter virus is known to improve cell killing that can be attributed to the presence of the oncolysis-enhancing Ad death protein. The more precise mechanism by which CRAds kill tumor cells is unclear, and the role of the host cell apoptotic machinery in this process has been addressed only in a limited way. Here, we examine the role of several major apoptotic pathways in the CRAd-induced killing of non-small-cell lung cancer H460 cells. As expected, CRAd(E3+) was more potent than CRAd(E3–). No evidence for the involvement of the p53-Bax apoptotic pathway was found. Western blot analyses demonstrated strong suppression of p53 expression and unchanged Bax levels during viral replication, and stable overexpression of human papillomavirus type 16-E6 in H460 cells did not affect killing by both CRAds. CRAd activity was also not hampered by stable overexpression of anti-apoptotic Bcl2 or BclXL, and endogenous Bcl2/BclXL protein levels remained constant during the oncolytic cycle. Some evidence for caspase processing was obtained at late time points after infection; however, the inhibition of caspases by the X-linked inhibitor of apoptosis protein overexpression or cotreatment with zVAD-fmk did not inhibit CRAd-dependent cell death. Analyses of several apoptotic features revealed no evidence for nuclear fragmentation or DNA laddering, although phosphatidylserine externalization was detected. We conclude that despite the known apoptosis-modulating abilities of individual Ad proteins, Ad5-{Delta}24-based CRAds trigger necrosis-like cell death. In addition, we propose that deregulated apoptosis in cancer cells, a possible drug resistance mechanism, provides no barrier for CRAd efficacy.

* Corresponding author. Mailing address: VU University Medical Center, Department of Medical Oncology, Room Br 232, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Phone: 31 20 444 3374. Fax: 31 20 444 3844. E. mail: kruyt{at}vumc.nl.

Journal of Virology, November 2004, p. 12243-12251, Vol. 78, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.22.12243-12251.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Leitner, S., Sweeney, K., Oberg, D., Davies, D., Miranda, E., Lemoine, N. R., Hallden, G. (2009). Oncolytic Adenoviral Mutants with E1B19K Gene Deletions Enhance Gemcitabine-induced Apoptosis in Pancreatic Carcinoma Cells and Anti-Tumor Efficacy In vivo. Clin. Cancer Res. 15: 1730-1740 [Abstract] [Full Text]  
  • Wu, C.-L., Shieh, G.-S., Chang, C.-C., Yo, Y.-T., Su, C.-H., Chang, M.-Y., Huang, Y.-H., Wu, P., Shiau, A.-L. (2008). Tumor-Selective Replication of an Oncolytic Adenovirus Carrying Oct-3/4 Response Elements in Murine Metastatic Bladder Cancer Models. Clin. Cancer Res. 14: 1228-1238 [Abstract] [Full Text]  
  • Dong, F., Wang, L., Davis, J. J., Hu, W., Zhang, L., Guo, W., Teraishi, F., Ji, L., Fang, B. (2006). Eliminating Established Tumor in nu/nu Nude Mice by a Tumor Necrosis Factor-{alpha}-Related Apoptosis-Inducing Ligand-Armed Oncolytic Adenovirus. Clin. Cancer Res. 12: 5224-5230 [Abstract] [Full Text]  
  • Vaha-Koskela, M. J.V., Kallio, J. P., Jansson, L. C., Heikkila, J. E., Zakhartchenko, V. A., Kallajoki, M. A., Kahari, V.-M., Hinkkanen, A. E. (2006). Oncolytic capacity of attenuated replicative semliki forest virus in human melanoma xenografts in severe combined immunodeficient mice.. Cancer Res. 66: 7185-7194 [Abstract] [Full Text]  
  • Mantwill, K., Kohler-Vargas, N., Bernshausen, A., Bieler, A., Lage, H., Kaszubiak, A., Surowiak, P., Dravits, T., Treiber, U., Hartung, R., Gansbacher, B., Holm, P. S. (2006). Inhibition of the Multidrug-Resistant Phenotype by Targeting YB-1 with a Conditionally Oncolytic Adenovirus: Implications for Combinatorial Treatment Regimen with Chemotherapeutic Agents.. Cancer Res. 66: 7195-7202 [Abstract] [Full Text]  
  • Ito, H., Aoki, H., Kuhnel, F., Kondo, Y., Kubicka, S., Wirth, T., Iwado, E., Iwamaru, A., Fujiwara, K., Hess, K. R., Lang, F. F., Sawaya, R., Kondo, S. (2006). Autophagic cell death of malignant glioma cells induced by a conditionally replicating adenovirus.. JNCI J Natl Cancer Inst 98: 625-636 [Abstract] [Full Text]  
  • Glockzin, G., Mantwill, K., Jurchott, K., Bernshausen, A., Ladhoff, A., Royer, H.-D., Gansbacher, B., Holm, P. S. (2006). Characterization of the Recombinant Adenovirus Vector AdYB-1: Implications for Oncolytic Vector Development.. J. Virol. 80: 3904-3911 [Abstract] [Full Text]  
  • Subramanian, T., Vijayalingam, S., Chinnadurai, G. (2006). Genetic Identification of Adenovirus Type 5 Genes That Influence Viral Spread. J. Virol. 80: 2000-2012 [Abstract] [Full Text]  
  • Gillet, L., Dewals, B., Farnir, F., de Leval, L., Vanderplasschen, A. (2005). Bovine Herpesvirus 4 Induces Apoptosis of Human Carcinoma Cell Lines In vitro and In vivo. Cancer Res. 65: 9463-9472 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»