Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo.
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.
Yang
Lihua
L
Department of Pediatrics, and Neurology and Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
Jackson
Erin
E
Woerner
B Mark
BM
Perry
Arie
A
Piwnica-Worms
David
D
Rubin
Joshua B
JB
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D000242:Cyclic AMP / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines; D019718:Receptors, CXCR4; D000242:Cyclic AMP; D020889:Rolipram