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Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine

J Taipale1, J K Chen, M K Cooper

  • 1Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Nature
|September 13, 2000
PubMed

Insights

Cyclopamine, a plant-derived compound, inhibits the Hedgehog (Hh) signaling pathway. This compound shows potential as a therapeutic agent for various human tumors driven by Smoothened (SMO) or Patched (PTCH) mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Mutations in Smoothened (SMO) or Patched (PTCH) genes activate the Hedgehog (Hh) signaling pathway.
  • This aberrant Hh pathway activity is implicated in the development of various human tumors, including basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma.

Purpose of the Study:

  • To investigate the therapeutic potential of cyclopamine, a plant-derived inhibitor of the Hh pathway.
  • To determine if cyclopamine can block Hh pathway activation and abnormal cell growth in tumors driven by SMO or PTCH mutations.

Main Methods:

  • Treatment of tumor cells with cyclopamine and its synthetic derivatives.
  • Assessment of Hh pathway activity and cell growth inhibition.

Main Results:

  • Cyclopamine effectively inhibits the Hh response pathway.
  • Cyclopamine and its derivatives block abnormal cell growth in tumors with oncogenic SMO or PTCH mutations.
  • Cyclopamine's mechanism may involve modulating the balance of active and inactive Smoothened forms.

Conclusions:

  • Cyclopamine is a potential mechanism-based therapeutic agent for SMO- and PTCH-driven tumors.
  • Synthetic derivatives of cyclopamine offer improved potency for cancer treatment.
  • Targeting the Hh pathway with cyclopamine presents a promising strategy for oncological therapies.

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