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Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth

Ada Girnita1, Leonard Girnita, Fabrizio del Prete

  • 1Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden.

Cancer Research
|January 20, 2004
PubMed

Insights

Certain cyclolignans, like picropodophyllin (PPP), selectively inhibit the insulin-like growth factor-1 receptor (IGF-1R) by blocking tyrosine phosphorylation. This discovery offers a promising new strategy for developing targeted cancer therapies without adverse effects on the insulin receptor.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The insulin-like growth factor-1 receptor (IGF-1R) is a key target for cancer therapy due to its role in malignant cell growth and survival.
  • Developing selective IGF-1R inhibitors is challenging due to its high homology with the insulin receptor, leading to potential diabetic side effects.
  • Current strategies focus on inhibitors that interfere with receptor autophosphorylation at the substrate level rather than ATP binding.

Purpose of the Study:

  • To investigate the potential of cyclolignans and related molecules as selective inhibitors of IGF-1R tyrosine phosphorylation.
  • To evaluate the efficacy and safety of picropodophyllin (PPP) as a potential anticancer agent targeting IGF-1R.

Main Methods:

  • Screening of cyclolignans for their ability to inhibit IGF-1R activity.
  • Assessing the effects of PPP on IGF-1R signaling pathways (pAkt, pErk1/2) in tumor cells.
  • Evaluating the in vivo efficacy of PPP in xenograft and allograft mouse models.
  • In vitro kinase assays and molecular modeling to determine the mechanism of action.

Main Results:

  • Certain cyclolignans, notably picropodophyllin (PPP), demonstrated potent and selective inhibition of IGF-1R tyrosine phosphorylation.
  • PPP showed low toxicity (LD(50) >500 mg/kg in rodents) and effectively reduced downstream signaling (pAkt, pErk1/2) in IGF-1R-positive tumor cells.
  • PPP treatment led to apoptosis in cultured tumor cells and complete tumor regression in mouse models.
  • PPP did not inhibit the insulin receptor or compete with ATP, suggesting substrate-level inhibition.

Conclusions:

  • Cyclolignans, particularly PPP, are effective and selective inhibitors of IGF-1R.
  • PPP exhibits significant anticancer activity with a favorable safety profile, making it a promising lead compound for developing novel cancer therapeutics.
  • Targeting IGF-1R at the substrate level offers a viable strategy to overcome the limitations of traditional ATP-competitive inhibitors.

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