Dual activity lysophosphatidic acid receptor pan-antagonist/autotaxin inhibitor reduces breast cancer cell migration in vitro and causes tumor regression in vivo.
Signal transduction modifiers that modulate the lysophosphatidic acid (LPA) pathway have potential as anticancer agents. Herein, we describe metabolically stabilized LPA analogues that reduce cell migration and invasion and cause regression of orthotopic breast tumors in vivo. Two diastereoisomeric alpha-bromophosphonates (BrP-LPA) were synthesized, and the pharmacology was determined for five LPA G protein-coupled receptors (GPCRs). The syn and anti diastereomers of BrP-LPA are pan-LPA GPCR antagonists and are also nanomolar inhibitors of the lysophospholipase D activity of autotaxin, the dominant biosynthetic source of LPA. Computational models correctly predicted the diastereoselectivity of antagonism for three GPCR isoforms. The anti isomer of BrP-LPA was more effective than syn isomer in reducing migration of MDA-MB-231 cells, and the anti isomer was superior in reducing invasion of these cells. Finally, orthotopic breast cancer xenografts were established in nude mice by injection of MB-231 cells in an in situ cross-linkable extracellular matrix. After 2 weeks, mice were treated with the BrP-LPA alone (10 mg/kg), Taxol alone (10 mg/kg), or Taxol followed by BrP-LPA. All treatments significantly reduced tumor burden, and BrP-LPA was superior to Taxol in reducing blood vessel density in tumors. Moreover, both the anti- and syn-BrP-LPA significantly reduced tumors at 3 mg/kg.
Zhang
Honglu
H
Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84108, USA.
Xu
Xiaoyu
X
Gajewiak
Joanna
J
Tsukahara
Ryoko
R
Fujiwara
Yuko
Y
Liu
Jianxiong
J
Fells
James I
JI
Perygin
Donna
D
Parrill
Abby L
AL
Tigyi
Gabor
G
Prestwich
Glenn D
GD
D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000627:therapeutic use*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000627:therapeutic use*; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors*; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors*; D000099189:Lysophospholipase D
D008246:Lysophospholipids; D009097:Multienzyme Complexes; D063065:Organophosphonates; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C512992:LPAR5 protein, human; C032881:lysophosphatidic acid