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Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling

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

癌症（英文版）2011，Vol.30Issue(7)：472-481,10.
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癌症（英文版）2011，Vol.30Issue(7)：472-481,10.DOI:10.5732/cjc.011.10157

Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling

Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling

Qipeng Fan 1Arash Garrossian 2Massoud Garrossian 2Dale Gardner 3Jingwu Xie 1Dongsheng Gu 1Miao He 1Hailan Liu 4Tao Sheng 1Guorui Xie 1Ching-xin Li 1Xiaoli Zhang 5Brandon Wainwright1

作者信息

  • 1. Wells Center for Pediatric Research, Department of Pediatrics and The Simon Cancer Center, Indiana University,Indianapolis, IN 46202, USA
  • 2. Logan Natural Products Inc., Dallas, TX 75025, USA
  • 3. United States Department of Agriculture, Agriculture Research Services,Poisonous Plant Research Laboratory, Logan, UT 84341, USA
  • 4. Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology,Wuhan University, Wuhan,Hubei 430079,P. R. China
  • 5. Department of Dermatology Xijing Hospital, Xi'an, Shaanxi 710032, P.R. China
  • 折叠

摘要

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 (LD<,50>) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T<,1/2>) 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 (IC<,50> = 50nmol/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:Ptch1<'neo/neo>and K14cre:SmoM2<'YFP>). 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.

关键词

Cyclopamine tartrate/hedgehog/smoothened/cancer therapy/mouse model

Key words

Cyclopamine tartrate/hedgehog/smoothened/cancer therapy/mouse model

引用本文复制引用

Qipeng Fan,Arash Garrossian,Massoud Garrossian,Dale Gardner,Jingwu Xie,Dongsheng Gu,Miao He,Hailan Liu,Tao Sheng,Guorui Xie,Ching-xin Li,Xiaoli Zhang,Brandon Wainwright..Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling[J].癌症（英文版）,2011,30(7):472-481,10.

基金项目

This research was supported by a grant from the National Institute of Health,USA(No.R01-CA94160). （No.R01-CA94160）

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