Volume 142, Issue 1, April 2014, Pages 126–139
Abstract
Artemisinins are a family of sesquiterpene trioxane lactone anti-malarial agents originally derived from Artemisia annua
L. The anti-malarial action of artemisinins involves the formation of
free radicals via cleavage of the endoperoxide bond in its structure,
which mediate eradication of the Plasmodium species. With its
established safety record in millions of malarial patients, artemisinins
are also being investigated in diseases like infections, cancers and
inflammation. Artemisinins have been reported to possess robust
inhibitory effects against viruses (e.g. Human cytomegalovirus), protozoa (e.g. Toxoplasma gondii), helminths (e.g. Schistosoma species and Fasciola hepatica) and fungi (e.g. Cryptococcus neoformans).
Artemisinins have demonstrated cytotoxic effects against a variety of
cancer cells by inducing cell cycle arrest, promoting apoptosis,
preventing angiogenesis, and abrogating cancer invasion and metastasis.
Artemisinins have been evaluated in animal models of autoimmune
diseases, allergic disorders and septic inflammation. The
anti-inflammatory effects of artemisinins have been attributed to the
inhibition of Toll-like receptors, Syk tyrosine kinase, phospholipase
Cγ, PI3K/Akt, MAPK, STAT-1/3/5, NF-κB, Sp1 and Nrf2/ARE signaling
pathways. This review provides a comprehensive update on non-malarial
use of artemisinins, modes of action of artemisinins in different
disease conditions, and drug development of artemisinins beyond
anti-malarial. With the concerted efforts in the novel synthesis of
artemisinin analogs and clinical pharmacology of artemisinins, it is
likely that artemisinin drugs will become a major armamentarium
combating a variety of human diseases beyond malaria.
Keywords
- Dihydroartemisinin;
- Artesunate;
- Infection;
- Cancer;
- Autoimmune disorder;
- Allergy
Abbreviations
- Bcl-2, B-cell lymphoma 2;
- CMV, cytomegalovirus;
- CDK, cyclin-dependent kinase;
- DHA, dihydroartemisinin;
- dsDNA, double-stranded DNA;
- HBV, hepatitis B virus;
- HIF-1α, hypoxia-inducible factor 1α;
- MAPK, mitogen-activated protein kinase;
- MCP-1, monocyte chemoattractant protein-1;
- MMP, matrix metalloproteinase;
- MRSA, methicillin-resistant Staphylococcus aureus;
- NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells;
- Nrf-2, Nuclear factor (erythroid-derived 2)-like 2;
- PI3K, phosphatidylinositide 3-kinase;
- PZQ, praziquantel;
- ROS, reactive oxygen species;
- SERCA, sarcoplasmic, endoplasmic reticulum PfATPase6 calcium pump;
- SLE, systemic lupus erythematosus;
- Syk, spleen tyrosine kinase;
- TfR, transferrin receptor;
- TIMP, tissue inhibitor of metalloproteinase;
- TLR, toll-like receptor;
- TNF-α, tumor necrosis factor-α;
- VEGF, vascular endothelial growth factor
- Corresponding
author at: Immunology Program, 28 Medical Drive, #03-05, Center for
Life Sciences, National University of Singapore, Singapore 117456,
Singapore. Tel.:
+ 65 6516 3263; fax: + 65 6873 7690.
Copyright © 2013 Elsevier Inc. All rights reserved.
