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Advances with phospholipid signalling as a target for anticancer drug development
G Powis1, M Berggren, A Gallegos
1Arizona Cancer Center, University of Arizona, Tucson 85724, USA.
Abstract:
The phosphatidylinositol-3-kinases (PtdIns-3-kinase) are a family of enzymes involved in the control of cell replication. One member of the family, the mammalian p110/p85 PtdIns-3-kinase, is a potential target for anticancer drug development because of its role as a component of growth factor and oncogene activated signalling pathways. There are a number of inhibitors of this PtdIns-3-kinase, the most potent being wortmannin (IC50 4 nM). Wortmannin inhibits cancer cell growth and has shown activity against mouse and human tumor xenografts in mice. Other inhibitors of the PtdIns-3-kinase are halogenated quinones which also inhibit cancer cell growth and have some in vivo antitumor activity. Some D-3-deoxy-3-substituted myo-inositol analogues and their corresponding PtdIns analogues have been synthesized. They may act as myo-inositol antimetabolites in the PtdIns-3-kinase pathway and they can inhibit cancer cell growth.
Insights
Phosphatidylinositol-3-kinases (PtdIns-3-kinase) are key in cell replication and cancer growth. Inhibitors like wortmannin show promise in anticancer drug development by blocking these pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Phosphatidylinositol-3-kinases (PtdIns-3-kinase) regulate cell replication.
- The mammalian p110/p85 PtdIns-3-kinase is implicated in growth factor and oncogene signaling pathways.
- This enzyme is a potential target for novel anticancer therapeutics.
Purpose of the Study:
- To review inhibitors of PtdIns-3-kinase for anticancer drug development.
- To highlight the efficacy of wortmannin and other inhibitors against cancer cell growth.
- To explore novel myo-inositol analogues as potential antimetabolites in the PtdIns-3-kinase pathway.
Main Methods:
- Review of existing literature on PtdIns-3-kinase inhibitors.
- Analysis of data on wortmannin's potency (IC50 4 nM) and in vivo antitumor activity.
- Synthesis and evaluation of D-3-deoxy-3-substituted myo-inositol analogues and PtdIns analogues.
Main Results:
- Wortmannin is a potent PtdIns-3-kinase inhibitor, demonstrating efficacy against tumor xenografts.
- Halogenated quinones also inhibit cancer cell growth and exhibit in vivo antitumor activity.
- Synthesized myo-inositol analogues act as antimetabolites, inhibiting cancer cell proliferation.
Conclusions:
- PtdIns-3-kinase inhibitors, including wortmannin and halogenated quinones, represent promising anticancer agents.
- Novel myo-inositol analogues offer a potential new class of antimetabolites targeting the PtdIns-3-kinase pathway.
- Targeting PtdIns-3-kinase signaling is a viable strategy for developing new cancer therapies.