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Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastoma
Shucheng Yin1, Ada Girnita, Thomas Strömberg
1Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, 17176 Stockholm, Sweden.
Abstract:
Glioblastoma (GB) is the most common malignant brain tumor in adults. It has limited treatment opportunities and is almost exclusively fatal. Owing to the central role the insulin-like growth factor-1 receptor (IGF-1R) plays in malignant cells, it has been suggested as a target for anticancer therapy including GB. The cyclolignan picropodophyllin (PPP) inhibits IGF-1R without affecting the highly homologous insulin receptor. Here, we show that PPP inhibits growth of human GB cell lines along with reduced phosphorylation of IGF-1R and AKT. In vivo, PPP-treatment causes dramatic tumor regression not only in subcutaneous xenografts but also in intracerebral xenografts, indicating passage of PPP across the blood-brain barrier.
Insights
Picropodophyllin (PPP) effectively inhibits glioblastoma (GB) growth by targeting the insulin-like growth factor-1 receptor (IGF-1R). This novel therapy shows promise, crossing the blood-brain barrier to reduce tumor size in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Neuro-oncology
Background:
- Glioblastoma (GB) is an aggressive adult brain tumor with poor prognosis.
- The insulin-like growth factor-1 receptor (IGF-1R) is crucial for malignant cell proliferation.
- Targeting IGF-1R presents a potential therapeutic strategy for glioblastoma.
Purpose of the Study:
- To investigate the efficacy of picropodophyllin (PPP) as an IGF-1R inhibitor for glioblastoma treatment.
- To evaluate PPP's effects on glioblastoma cell growth and signaling pathways.
- To assess PPP's in vivo anti-tumor activity and blood-brain barrier penetration.
Main Methods:
- Treatment of human glioblastoma cell lines with PPP.
- Assessment of IGF-1R and AKT phosphorylation.
- Evaluation of PPP efficacy in subcutaneous and intracerebral glioblastoma xenograft models.
Main Results:
- PPP inhibited human glioblastoma cell line growth.
- PPP treatment reduced IGF-1R and AKT phosphorylation.
- Significant tumor regression was observed in both subcutaneous and intracerebral xenografts.
- PPP demonstrated ability to cross the blood-brain barrier.
Conclusions:
- Picropodophyllin (PPP) is a potent inhibitor of glioblastoma growth.
- Targeting IGF-1R with PPP offers a promising therapeutic avenue for glioblastoma.
- PPP's ability to penetrate the blood-brain barrier is critical for its efficacy in brain tumors.
