This Article Full Text Full Text (PDF) Supplementary Data 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 Yang, L. Articles by Rubin, J. B. Search for Related Content PubMed PubMed Citation Articles by Yang, L. Articles by Rubin, J. B.

Blocking CXCR4-Mediated Cyclic AMP Suppression Inhibits Brain Tumor Growth In vivo

Departments of ¹ Pediatrics, ² Pathology and Immunology, ³ Molecular Biology and Pharmacology, ⁴ Anatomy and Neurobiology, and ⁵ Neurology and ⁶ Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri

Requests for reprints: Joshua B. Rubin, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Washington University School of Medicine, Campus Box 8208, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: 314-286-2790; Fax: 314-286-2892; E-mail: Rubin_J{at}kids.wustl.edu.

The chemokine CXCL12 and its cognate receptor CXCR4 regulate malignant brain tumor growth and are potential chemotherapeutic targets. However, the molecular basis for CXCL12-induced tumor growth remains unclear, and the optimal approach to inhibiting CXCR4 function in cancer is unknown. To develop such a therapeutic approach, we investigated the signaling pathways critical for CXCL12 function in normal and malignant cells. We discovered that CXCL12-dependent tumor growth is dependent upon sustained inhibition of cyclic AMP (cAMP) production, and that the antitumor activity of the specific CXCR4 antagonist AMD 3465 is associated with blocking cAMP suppression. Consistent with these findings, we show that pharmacologic elevation of cAMP with the phosphodiesterase inhibitor Rolipram suppresses tumor cell growth in vitro and, upon oral administration, inhibits intracranial growth in xenograft models of malignant brain tumors with comparable efficacy to AMD 3465. These data indicate that the clinical evaluation of phosphodiesterase inhibitors in the treatment of patients with brain tumors is warranted. [Cancer Res 2007;67(2):651–8]

This article has been cited by other articles:

				J. Kwong, H. Kulbe, D. Wong, P. Chakravarty, and F. Balkwill An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cells Mol. Cancer Ther., July 1, 2009; 8(7): 1893 - 1905. [Abstract] [Full Text] [PDF]

				N. M. Warrington and J. B. Rubin Phosphodiesterase-4 Inhibition and Brain Tumor Growth Clin. Cancer Res., May 1, 2009; 15(9): 3238 - 3238. [Full Text] [PDF]

				R. Sengupta, S. Burbassi, S. Shimizu, S. Cappello, R. B. Vallee, J. B. Rubin, and O. Meucci Morphine Increases Brain Levels of Ferritin Heavy Chain Leading to Inhibition of CXCR4-Mediated Survival Signaling in Neurons J. Neurosci., February 25, 2009; 29(8): 2534 - 2544. [Abstract] [Full Text] [PDF]

				D. Wong and W. Korz Translating an Antagonist of Chemokine Receptor CXCR4: From Bench to Bedside Clin. Cancer Res., December 15, 2008; 14(24): 7975 - 7980. [Abstract] [Full Text] [PDF]

				P. Goldhoff, N. M. Warrington, D. D. Limbrick Jr., A. Hope, B. M. Woerner, E. Jackson, A. Perry, D. Piwnica-Worms, and J. B. Rubin Targeted Inhibition of Cyclic AMP Phosphodiesterase-4 Promotes Brain Tumor Regression Clin. Cancer Res., December 1, 2008; 14(23): 7717 - 7725. [Abstract] [Full Text] [PDF]

				D. H. Gutmann Using Neurofibromatosis-1 to Better Understand and Treat Pediatric Low-Grade Glioma J Child Neurol, October 1, 2008; 23(10): 1186 - 1194. [Abstract] [PDF]

				V. De Falco, V. Guarino, E. Avilla, M. D. Castellone, P. Salerno, G. Salvatore, P. Faviana, F. Basolo, M. Santoro, and R. M. Melillo Biological Role and Potential Therapeutic Targeting of the Chemokine Receptor CXCR4 in Undifferentiated Thyroid Cancer Cancer Res., December 15, 2007; 67(24): 11821 - 11829. [Abstract] [Full Text] [PDF]

				N. M. Warrington, B. M. Woerner, G. C. Daginakatte, B. Dasgupta, A. Perry, D. H. Gutmann, and J. B. Rubin Spatiotemporal Differences in CXCL12 Expression and Cyclic AMP Underlie the Unique Pattern of Optic Glioma Growth in Neurofibromatosis Type 1 Cancer Res., September 15, 2007; 67(18): 8588 - 8595. [Abstract] [Full Text] [PDF]