A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors.
The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors.
Rubin
Joshua B
JB
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Kung
Andrew L
AL
Klein
Robyn S
RS
Chan
Jennifer A
JA
Sun
YanPing
Y
Schmidt
Karl
K
Kieran
Mark W
MW
Luster
Andrew D
AD
Segal
Rosalind A
RA
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D017209:Apoptosis; D001596:Benzylamines; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis; D002633:Chemotaxis; D000080027:Cyclams; D005909:Glioblastoma / Q000188:drug therapy; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008156:Luciferases / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008527:Medulloblastoma / Q000188:drug therapy; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
D019380:Anti-HIV Agents; D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; D008156:Luciferases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C088327:plerixafor