This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gupta, A. K. Articles by Muschel, R. J. Search for Related Content PubMed PubMed Citation Articles by Gupta, A. K. Articles by Muschel, R. J.

HIV Protease Inhibitors Block Akt Signaling and Radiosensitize Tumor Cells Both In vitro and In vivo

Departments of ¹ Radiation and ² Biostatistics and Epidemiology, University of Pennsylvania; ³ Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Requests for reprints: Anjali K. Gupta, Department of Radiation Oncology, University of Pennsylvania, 195 JMB, 3620 Hamilton Walk, Philadelphia, PA 19104. Phone: 215-898-0076; Fax: 215-898-0996; E-mail: gupta{at}xrt.upenn.edu.

In tumor cells with mutations in epidermal growth factor receptor (SQ20B), H-Ras (T24), or K-Ras (MIAPACA2 and A549), the inhibition of Akt phosphorylation increases radiation sensitivity in clonogenic assays, suggesting that Akt is a potential molecular target when combined with therapeutic radiation. Insulin resistance and diabetes are recognized side effects of HIV protease inhibitors (HPIs), suggesting that these agents may inhibit Akt signaling. Because activation of the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is common in human cancers, we hypothesized that HPIs can inhibit Akt activity resulting in increased tumor cell sensitivity to ionizing radiation–induced cell death. Five first-generation HPIs were subsequently tested and three of the five (amprenavir, nelfinavir, and saquinavir but not ritonavir or indinavir) inhibited Akt phosphorylation at Ser⁴⁷³ at serum concentrations routinely achieved in HIV patients. In both tumor cell colony formation assays and tumor regrowth delay experiments, combinations of drug and radiation exerted synergistic effects compared with either modality alone. In addition, in vivo, doses of amprenavir or nelfinavir comparable with the therapeutic levels achieved in HIV patients were sufficient to down-regulate phosphorylation of Akt in SQ20B and T24 xenografts. Finally, overexpression of active PI3K in cells without activation of Akt resulted in radiation resistance that could be inhibited with HPIs. Because there is abundant safety data on HPIs accumulated in thousands of HIV patients over the last 5 years, these agents are excellent candidates to be tested as radiation sensitizers in clinical trials.

This article has been cited by other articles:

				T. B. Brunner, M. Geiger, G. G. Grabenbauer, M. Lang-Welzenbach, T. S. Mantoni, A. Cavallaro, R. Sauer, W. Hohenberger, and W. G. McKenna Phase I Trial of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir and Chemoradiation for Locally Advanced Pancreatic Cancer J. Clin. Oncol., June 1, 2008; 26(16): 2699 - 2706. [Abstract] [Full Text] [PDF]

				P. Pyrko, A. Kardosh, W. Wang, W. Xiong, A. H. Schonthal, and T. C. Chen HIV-1 Protease Inhibitors Nelfinavir and Atazanavir Induce Malignant Glioma Death by Triggering Endoplasmic Reticulum Stress Cancer Res., November 15, 2007; 67(22): 10920 - 10928. [Abstract] [Full Text] [PDF]

				S. J. Libertini, C. G. Tepper, V. Rodriguez, D. M. Asmuth, H.-J. Kung, and M. Mudryj Evidence for Calpain-Mediated Androgen Receptor Cleavage as a Mechanism for Androgen Independence Cancer Res., October 1, 2007; 67(19): 9001 - 9005. [Abstract] [Full Text] [PDF]

				J. J. Gills, J. LoPiccolo, J. Tsurutani, R. H. Shoemaker, C. J.M. Best, M. S. Abu-Asab, J. Borojerdi, N. A. Warfel, E. R. Gardner, M. Danish, et al. Nelfinavir, A Lead HIV Protease Inhibitor, Is a Broad-Spectrum, Anticancer Agent that Induces Endoplasmic Reticulum Stress, Autophagy, and Apoptosis In vitro and In vivo Clin. Cancer Res., September 1, 2007; 13(17): 5183 - 5194. [Abstract] [Full Text] [PDF]

				K. C. Cuneo, T. Tu, L. Geng, A. Fu, D. E. Hallahan, and C. D. Willey HIV Protease Inhibitors Enhance the Efficacy of Irradiation Cancer Res., May 15, 2007; 67(10): 4886 - 4893. [Abstract] [Full Text] [PDF]

				Z. Jiang, N. Pore, G. J. Cerniglia, R. Mick, M.-M. Georgescu, E. J. Bernhard, S. M. Hahn, A. K. Gupta, and A. Maity Phosphatase and Tensin Homologue Deficiency in Glioblastoma Confers Resistance to Radiation and Temozolomide that Is Reversed by the Protease Inhibitor Nelfinavir Cancer Res., May 1, 2007; 67(9): 4467 - 4473. [Abstract] [Full Text] [PDF]

				W. Jiang, P. J. Mikochik, J. H. Ra, H. Lei, K. T. Flaherty, J. D. Winkler, and F. R. Spitz HIV Protease Inhibitor Nelfinavir Inhibits Growth of Human Melanoma Cells by Induction of Cell Cycle Arrest Cancer Res., February 1, 2007; 67(3): 1221 - 1227. [Abstract] [Full Text] [PDF]

				N. Pore, A. K. Gupta, G. J. Cerniglia, Z. Jiang, E. J. Bernhard, S. M. Evans, C. J. Koch, S. M. Hahn, and A. Maity Nelfinavir Down-regulates Hypoxia-Inducible Factor 1{alpha} and VEGF Expression and Increases Tumor Oxygenation: Implications for Radiotherapy. Cancer Res., September 15, 2006; 66(18): 9252 - 9259. [Abstract] [Full Text] [PDF]