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. Cyc...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.展开更多
Plants toxic to livestock species have a significantly negative impact on agriculture but can be an important source of bioactive molecules for use in medicine.The initial research on plant toxicity is focused on the ...Plants toxic to livestock species have a significantly negative impact on agriculture but can be an important source of bioactive molecules for use in medicine.The initial research on plant toxicity is focused on the response to the poisoning and the specific livestock species impacted by the toxic plant.This research emphasizes the identification of the plant and natural product(s)responsible for the toxicity to livestock,the prevention of further poisonings,and the development of treatments for the affected animals.Once the bioactive molecules impacting the livestock species have been identified,research on these compounds is then focused on determining the mechanism of action,the development of models for further study,and the identification of potential drug candidates for the treatment of disease.Specific examples of the agricultural-based research that are relevant to Human and Veterinary Medicine include:cyclopamine from Veratrum californicum(western false hellebore),piperidine alkaloids fromLupinus species(lupines),and cicutoxin from Cicuta species(water hemlock).展开更多
基金supported by a grant from the National Institute of Health, USA (No. R01-CA94160)
文摘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.
文摘Plants toxic to livestock species have a significantly negative impact on agriculture but can be an important source of bioactive molecules for use in medicine.The initial research on plant toxicity is focused on the response to the poisoning and the specific livestock species impacted by the toxic plant.This research emphasizes the identification of the plant and natural product(s)responsible for the toxicity to livestock,the prevention of further poisonings,and the development of treatments for the affected animals.Once the bioactive molecules impacting the livestock species have been identified,research on these compounds is then focused on determining the mechanism of action,the development of models for further study,and the identification of potential drug candidates for the treatment of disease.Specific examples of the agricultural-based research that are relevant to Human and Veterinary Medicine include:cyclopamine from Veratrum californicum(western false hellebore),piperidine alkaloids fromLupinus species(lupines),and cicutoxin from Cicuta species(water hemlock).
