Cyclopamine treatment of full-blown Hh/Ptch-associated RMS partially inhibits Hh/Ptch signaling, but not tumor growth
- PMID: 17963245
- DOI: 10.1002/mc.20394
Cyclopamine treatment of full-blown Hh/Ptch-associated RMS partially inhibits Hh/Ptch signaling, but not tumor growth
Abstract
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.
(c) 2007 Wiley-Liss, Inc.
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