Effect of the Hedgehog-inhibitor cyclopamine on mice with osteosarcoma pulmonary metastases
Jörg Warzecha1, Daniela Dinges, Balasz Kaszap
1Department of Ortho-pedic Surgery, Johann Wolfgang Goethe-University Hospital, Marienburg-strasse 2, D-60528 Frankfurt, Germany. j.warzecha@friedrichsheim.de
Abstract:
Chemoresistant metastases of osteosarcoma in humans limit survival in approximately one third of patients. Furthermore, aggressive chemotherapy can lead to side effects and occurrence of secondary malignancies in long time survivors. Therefore, supplemental medical strategies are worthwhile. The well-directed manipulation of cancer-signaling-cascades is an appealing approach. Targeting of the Hedgehog-pathway in cancer has led to promising results in vitro as well as in vivo in a number of different tumor types. Recently, the impact of cyclopamine, which inhibits Hedgehog signaling by binding to the receptor Smoothened, was shown in different human osteosarcoma cell lines in vitro and in vivo. In the present study we examined the influence of cyclopamine on early pulmonary metastases in vivo. Murine osteosarcoma cells, OS-50, were injected into the lateral tail vein of young BALB/c mice. Treatment with subcutaneous cyclopamine injections began after three days. Two weeks later, the animals were sacrificed and the number of pulmonary metastases was counted. We could observe a trend towards decreased metastases in the cyclopamine group (~20%). On the other hand, remarkable side effects were caused by the cyclopamine/ethanol/triolein preparation (mainly skin ulcerations).
Insights
Cyclopamine showed a trend towards reducing osteosarcoma lung metastases in mice. However, significant side effects like skin ulcerations limit its potential as a supplemental cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemoresistant osteosarcoma metastases significantly limit patient survival.
- Aggressive chemotherapy for osteosarcoma can cause severe side effects and secondary cancers.
- Targeting cancer signaling pathways, like the Hedgehog pathway, offers a promising therapeutic avenue.
Purpose of the Study:
- To investigate the efficacy of cyclopamine, a Hedgehog pathway inhibitor, in reducing early pulmonary osteosarcoma metastases in a murine model.
- To assess the in vivo effects of cyclopamine on established osteosarcoma lung metastases.
Main Methods:
- Murine osteosarcoma cells (OS-50) were intravenously injected into BALB/c mice to establish pulmonary metastases.
- Mice received subcutaneous injections of cyclopamine starting three days post-injection.
- Pulmonary metastases were quantified after two weeks of treatment.
Main Results:
- A trend towards a decrease in pulmonary metastases (approximately 20%) was observed in the cyclopamine-treated group.
- The cyclopamine preparation caused notable side effects, primarily skin ulcerations.
Conclusions:
- Cyclopamine demonstrates a potential, albeit modest, inhibitory effect on osteosarcoma lung metastasis in vivo.
- Significant side effects associated with the cyclopamine preparation necessitate further investigation for safer therapeutic applications.
