Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling

Qipeng Fan, Dongsheng Gu, Miao He, Hailan Liu, Tao Sheng, Guorui Xie, Ching Xin Li, Xiaoli Zhang, Brandon Wainwright, Arash Garrossian, Massoud Garrossian, Dale Gardner, Jingwu Xie

Research output: Contribution to journalArticle

15 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)472-481
Number of pages10
JournalChinese Journal of Cancer
Issue number7
StatePublished - 2011


  • Cancer therapy
  • Cyclopamine tartrate
  • Hedgehog
  • Mouse model
  • Smoothened

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Fan, Q., Gu, D., He, M., Liu, H., Sheng, T., Xie, G., Li, C. X., Zhang, X., Wainwright, B., Garrossian, A., Garrossian, M., Gardner, D., & Xie, J. (2011). Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling. Chinese Journal of Cancer, 30(7), 472-481. https://doi.org/10.5732/cjc.011.10157