Document Detail

Inhibition of PI3K Signaling Spurs New Therapeutic Opportunities in Inflammatory/Autoimmune Diseases and Hematological Malignancies.
MedLine Citation:
PMID:  23023033     Owner:  NLM     Status:  In-Data-Review    
The phosphoinositide 3-kinase/mammalian target of rapamycin/protein kinase B (PI3K/mTOR/Akt) signaling pathway is central to a plethora of cellular mechanisms in a wide variety of cells including leukocytes. Perturbation of this signaling cascade is implicated in inflammatory and autoimmune disorders as well as hematological malignancies. Proteins within the PI3K/mTOR/Akt pathway therefore represent attractive targets for therapeutic intervention. There has been a remarkable evolution of PI3K inhibitors in the past 20 years from the early chemical tool compounds to drugs that are showing promise as anticancer agents in clinical trials. The use of animal models and pharmacological tools has expanded our knowledge about the contribution of individual class I PI3K isoforms to immune cell function. In addition, class II and III PI3K isoforms are emerging as nonredundant regulators of immune cell signaling revealing potentially novel targets for disease treatment. Further complexity is added to the PI3K/mTOR/Akt pathway by a number of novel signaling inputs and feedback mechanisms. These can present either caveats or opportunities for novel drug targets. Here, we consider recent advances in 1) our understanding of the contribution of individual PI3K isoforms to immune cell function and their relevance to inflammatory/autoimmune diseases as well as lymphoma and 2) development of small molecules with which to inhibit the PI3K pathway. We also consider whether manipulating other proximal elements of the PI3K signaling cascade (such as class II and III PI3Ks or lipid phosphatases) are likely to be successful in fighting off different immune diseases.
John G Foster; Matthew D Blunt; Edward Carter; Stephen G Ward
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Pharmacological reviews     Volume:  64     ISSN:  1521-0081     ISO Abbreviation:  Pharmacol. Rev.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-01     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0421737     Medline TA:  Pharmacol Rev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1027-54     Citation Subset:  IM    
Inflammatory Cell Biology Laboratory, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
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