Cyclopamine treatment of full-blown Hh/Ptch-associated RMS partially inhibits Hh/Ptch signaling, but not tumor growth.
Mutations in the Hedgehog (Hh) receptor Patched (Ptch) are responsible for a variety of tumors, which show ligand-independent stimulation of the Hh/Ptch signaling cascade. Cyclopamine is an alkaloid of the corn lily Veratrum californicum, which blocks activity of the pathway by inhibition of Smoothened (Smo), the signal transduction partner of Ptch. This results in growth inhibition of Hh/Ptch-dependent tumor cells in vitro, of subcutaneous xenografts as well as of precancerous lesions in Ptch(+/-) mice. However, the evidence that treatment with cyclopamine is an effective anti-cancer therapy against full-blown tumors is sparse. Here, we have investigated the responsiveness of full-blown Hh/Ptch-associated rhabdomyosarcoma (RMS) to this drug. Hh pathway activity and proliferation of cultured primary RMS cells was inhibited by cyclopamine. Hh signaling was also partially suppressed by the drug in RMS in vivo, but cyclopamine treatment did not result in stable disease or tumor regression. It also did not affect proliferation, apoptosis or the differentiation status of RMS. This was in contrast to anti-proliferative effects on tumor growth caused by doxorubicin, an anthracycline routinely used in therapy of human RMS. In summary, our data indicate that there must be additional factors that render full-blown Hh/Ptch-associated RMS insensitive against anti-proliferative effects of cyclopamine in vivo.
Ecke
Ines
I
Institute of Human Genetics, University of Goettingen, Goettingen, Germany.
Rosenberger
Albert
A
Obenauer
Silvia
S
Dullin
Christian
C
Aberger
Fritz
F
Kimmina
Sarah
S
Schweyer
Stefan
S
Hahn
Heidi
H
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000627:therapeutic use; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D015996:Survival Rate; D014704:Veratrum Alkaloids / Q000627:therapeutic use*; D000071676:Zinc Finger Protein GLI1
D000903:Antibiotics, Antineoplastic; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C513121:IGF2 protein, mouse; D051741:Kruppel-Like Transcription Factors; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D007335:Insulin-Like Growth Factor II; D004317:Doxorubicin; C000541:cyclopamine