title: Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling.
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: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.
authors: Wells Center for Pediatric Research, Department of Pediatrics and The Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA.
authors: Qipeng
authors: Q
authors: Fan
authors: Dongsheng
authors: D
authors: Gu
authors: Miao
authors: M
authors: He
authors: Hailan
authors: H
authors: Liu
authors: Tao
authors: T
authors: Sheng
authors: Guorui
authors: G
authors: Xie
authors: Ching-Xin
authors: CX
authors: Li
authors: Xiaoli
authors: X
authors: Zhang
authors: Brandon
authors: B
authors: Wainwright
authors: Arash
authors: A
authors: Garrossian
authors: Massoud
authors: M
authors: Garrossian
authors: Dale
authors: D
authors: Gardner
authors: Jingwu
authors: J
authors: Xie
mesh_terms: D000818:Animals; D002280:Basal Cell Carcinoma / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009046:Motor Neurons / Q000166:cytology; D010946:Plants, Medicinal / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000473:pathology*; D000072086:Smoothened Receptor; D012995:Solubility; D013644:Tartrates / Q000097:blood / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects*; D014703:Veratrum / Q000737:chemistry; D014704:Veratrum Alkaloids / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D013644:Tartrates; D014704:Veratrum Alkaloids; C029768:tartaric acid; C000541:cyclopamine