IGF-1 receptor inhibition by picropodophyllin in medulloblastoma.
The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression. We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.
Ohshima-Hosoyama
Sachiko
S
Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Hosoyama
Tohru
T
Nelon
Laura D
LD
Keller
Charles
C
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D053148:Caspase 3; D011034:Podophyllotoxin