Phosphatase-resistant analogues of lysophosphatidic acid: Agonists promote healing, antagonists and autotaxin inhibitors treat cancer

Glenn D. Prestwich, Joanna Gajewiak, Honglu Zhang, Xiaoyu Xu, Guanghui Yang, Monica Serban

Research output: Contribution to journalReview articlepeer-review

64 Scopus citations

Abstract

Isoform-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 or 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.

Original languageEnglish
Pages (from-to)588-594
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1781
Issue number9
DOIs
StatePublished - Sep 2008

Keywords

  • Aminooxy
  • Autotaxin
  • GPCR antagonist
  • Lysophospholipase D inhibitor
  • Methylene phosphonate
  • Phosphorothioate
  • Receptor isoform selectivity
  • Tumor regression

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