Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling

Fan, Qipeng, Gu, Dongsheng, He, Miao, Liu, Hailan, Sheng. Tao, Xie, Guorui, Li, Ching-xin, Zhang, Xaoili, Wainwright, Brandon J., Garrossian, Arash, Garrossian, Massoud, Gardner, Dale and Xie, Jingwu (2011) Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling. Chinese Journal of Cancer, 30 7: 472-481. doi:10.5732/cjc.011.10157

Author Fan, Qipeng
Gu, Dongsheng
He, Miao
Liu, Hailan
Sheng. Tao
Xie, Guorui
Li, Ching-xin
Zhang, Xaoili
Wainwright, Brandon J.
Garrossian, Arash
Garrossian, Massoud
Gardner, Dale
Xie, Jingwu
Title Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling
Journal name Chinese Journal of Cancer   Check publisher's open access policy
ISSN 1944-446X
Publication date 2011-07
Sub-type Article (original research)
DOI 10.5732/cjc.011.10157
Open Access Status DOI
Volume 30
Issue 7
Start page 472
End page 481
Total pages 10
Place of publication Austin, TX, United States
Publisher Landes Bioscience
Collection year 2012
Language eng
Formatted abstract
The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyclopamine (Cyc), an alkaloid from the Veratrum plant, is a specific natural product inhibitor of the Hh pathway that acts by targeting smoothened (SMO) protein. However, its poor solubility, acid sensitivity, and weak potency relative to other Hh antagonists prevent the clinical development of Cyc as a therapeutic agent. Here, we report properties of cyclopamine tartrate salt (CycT) and its activities in Hh signaling-mediated cancer in vitro and in vivo. Unlike Cyc, CycT is water soluble (5-10 mg/mL). The median lethal dose (LD50) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T1/2) of CycT was not significantly different from that of Cyc. We showed that CycT had a higher inhibitory activity for Hh signaling-dependent motor neuron differentiation than did Cyc (IC50 = 50 nmol/L for CycT vs. 300 nmol/L for Cyc). We also tested the antitumor effectiveness of these Hh inhibitors using two mouse models of basal cell carcinomas (K14cre:Ptch1neo/neo and K14cre:SmoM2YFP). After topical application of CycT or Cyc daily for 21 days, we found that all CycT-treated mice had tumor shrinkage and decreased expression of Hh target genes. Taken together, we found that CycT is an effective inhibitor of Hh signaling-mediated carcinogenesis.
Keyword Cyclopamine tartrate
Cancer therapy
Mouse model
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
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Created: Tue, 17 Jan 2012, 13:50:18 EST by Susan Allen on behalf of Institute for Molecular Bioscience