Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1781, Issue 9, Pages 588-594Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2008.03.008
Keywords
phosphorothioate; methylene phosphonate; aminooxy; autotaxin; lysophospholipase D inhibitor; receptor isoform selectivity; GPCR antagonist; tumor regression
Funding
- National Institutes of Health [NS29632, 313 rcs]
- Anderson Cancer Center
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lsoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G protein-coupled receptors (GPCRs) have important potential applications in cell biology and therapy. LPA GPCRs regulate cancer cell proliferation, invasion, angiogenesis, and also biochemical resistance to chemotherapy- and radiotherapy-induced apoptosis. LPA and its analogues also are feedback inhibitors of the enzyme lysophospholipase D (lysoPLD, a.k.a., autotaxin, ATX), a central regulator of invasion and metastasis. For cancer therapy, the optimal therapeutic profile Would be a metabolically-stabilized, pan-LPA receptor antagonist that also inhibited lysoPLD. For protection of gastrointestinal mucosa and lymphocytes, LPA agonists Would be desirable to minimize or reverse radiation OF chemical-induced injury. Analogues of lysophosphatidic acid (LPA) that are chemically modified to be less susceptible to phospholipases and phosphatases show activity as long-lived receptor-specific agonists and antagonists for LPA receptors, as well as inhibitors for the lysoPLD activity of ATX. (c) 2008 Elsevier B.V. All rights reserved.
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