TY - JOUR
T1 - Phosphatase-resistant analogues of lysophosphatidic acid
T2 - Agonists promote healing, antagonists and autotaxin inhibitors treat cancer
AU - Prestwich, Glenn D.
AU - Gajewiak, Joanna
AU - Zhang, Honglu
AU - Xu, Xiaoyu
AU - Yang, Guanghui
AU - Serban, Monica
N1 - Funding Information:
We thank the National Institutes of Health for grant NS29632 to G.D.P. We also thank our colleagues, G. Tigyi (U Tennessee, Memphis), J. Aoki (U Tokyo), A. Parrill (U Memphis), M. Murph and G. B. Mills (M. D. Anderson Cancer Center) for ongoing collaborative studies on biological activity in literature cited herein, and S. W. Nam (Catholic U, Korea) for providing the NIH 3T3 ras ATX cell line.
PY - 2008/9
Y1 - 2008/9
N2 - 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.
AB - 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.
KW - Aminooxy
KW - Autotaxin
KW - GPCR antagonist
KW - Lysophospholipase D inhibitor
KW - Methylene phosphonate
KW - Phosphorothioate
KW - Receptor isoform selectivity
KW - Tumor regression
UR - http://www.scopus.com/inward/record.url?scp=49949105271&partnerID=8YFLogxK
U2 - 10.1016/j.bbalip.2008.03.008
DO - 10.1016/j.bbalip.2008.03.008
M3 - Review article
C2 - 18454946
AN - SCOPUS:49949105271
SN - 1388-1981
VL - 1781
SP - 588
EP - 594
JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
JF - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
IS - 9
ER -
