This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Ikezoe, T. Articles by Koeffler, H. P. Search for Related Content PubMed PubMed Citation Articles by Ikezoe, T. Articles by Koeffler, H. P.

HIV-1 Protease Inhibitor, Ritonavir

A Potent Inhibitor of CYP3A4, Enhanced the Anticancer Effects of Docetaxel in Androgen-Independent Prostate Cancer Cells In vitro and In vivo

¹ Division of Hematology/Oncology, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, California; ² Department of Pathology, Center for Health Science, UCLA School of Medicine, Los Angeles, California; and Departments of ³ Internal Medicine and ⁴ Tumor Pathology, KMS, Kochi University, Kochi, Japan

We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all–trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes. The CYP3A4 is involved in drug metabolism and acquisition of drug resistance. To clarify the drug interaction between ritonavir and other anticancer drugs, we cultured DU145 cells with docetaxel either alone or in combination with ritonavir. Ritonavir enhanced the antiproliferative and proapoptotic effects of docetaxel in the hormonally independent DU145 prostate cancer cells in vitro as measured by the clonogenic soft agar assay and detection of the activated form of caspase-3 and cleavage of poly(ADP-ribose) polymerase using Western blot analysis. Real-time PCR showed that docetaxel induced the expression of CYP3A4 at the transcriptional level, and ritonavir (10^–5 mol/L) completely blocked this induction. An ELISA-based assay also showed that ritonavir inhibited DNA binding activity of nuclear factor B (NFB) in DU145 cells, which is a contributor to drug resistance in cancer cells. Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.

This article has been cited by other articles:

				W. R. L. de Campos, D. Coopusamy, L. Morris, B. M. Mayosi, and M. Khati Cytotoxicological Analysis of a gp120 Binding Aptamer with Cross-Clade Human Immunodeficiency Virus Type 1 Entry Inhibition Properties: Comparison to Conventional Antiretrovirals Antimicrob. Agents Chemother., July 1, 2009; 53(7): 3056 - 3064. [Abstract] [Full Text] [PDF]

				R. L. Oostendorp, A. Huitema, H. Rosing, R. S. Jansen, R. ter Heine, M. Keessen, J. H. Beijnen, and J. H.M. Schellens Coadministration of Ritonavir Strongly Enhances the Apparent Oral Bioavailability of Docetaxel in Patients with Solid Tumors Clin. Cancer Res., June 15, 2009; 15(12): 4228 - 4233. [Abstract] [Full Text] [PDF]

				D. Maksimovic-Ivanic, S. Mijatovic, D. Miljkovic, L. Harhaji-Trajkovic, G. Timotijevic, M. Mojic, D. Dabideen, K. F. Cheng, J. A. McCubrey, K. Mangano, et al. The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt Mol. Cancer Ther., May 1, 2009; 8(5): 1169 - 1178. [Abstract] [Full Text] [PDF]

				Z. He, L. Qin, L. Chen, N. Peng, J. You, and X. Chen Synergy of Human Immunodeficiency Virus Protease Inhibitors with Chloroquine against Plasmodium falciparum In Vitro and Plasmodium chabaudi In Vivo Antimicrob. Agents Chemother., July 1, 2008; 52(7): 2653 - 2656. [Abstract] [Full Text] [PDF]

				M. Kraus, E. Malenke, J. Gogel, H. Muller, T. Ruckrich, H. Overkleeft, H. Ovaa, E. Koscielniak, J. T. Hartmann, and C. Driessen Ritonavir induces endoplasmic reticulum stress and sensitizes sarcoma cells toward bortezomib-induced apoptosis Mol. Cancer Ther., July 1, 2008; 7(7): 1940 - 1948. [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]

				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]

				V. Esposito, E. Palescandolo, E. P. Spugnini, V. Montesarchio, A. De Luca, I. Cardillo, G. Cortese, A. Baldi, and A. Chirianni Evaluation of Antitumoral Properties of the Protease Inhibitor Indinavir in a Murine Model of Hepatocarcinoma Clin. Cancer Res., April 15, 2006; 12(8): 2634 - 2639. [Abstract] [Full Text] [PDF]

				A. Srirangam, R. Mitra, M. Wang, J. C. Gorski, S. Badve, L. Baldridge, J. Hamilton, H. Kishimoto, J. Hawes, L. Li, et al. Effects of HIV Protease Inhibitor Ritonavir on Akt-Regulated Cell Proliferation in Breast Cancer Clin. Cancer Res., March 15, 2006; 12(6): 1883 - 1896. [Abstract] [Full Text] [PDF]

				N. Agrawal, J. Pallos, N. Slepko, B. L. Apostol, L. Bodai, L.-W. Chang, A.-S. Chiang, L. M. Thompson, and J. L. Marsh Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila PNAS, March 8, 2005; 102(10): 3777 - 3781. [Abstract] [Full Text] [PDF]