title: Orally active lysophosphatidic acid receptor antagonist attenuates pancreatic cancer invasion and metastasis in vivo.
abstract: Pancreatic cancer is highly metastatic and has a poor prognosis. However, there is no established treatment for pancreatic cancer. Lysophosphatidic acid (LPA) has been shown to be present in effluents of cancers and involved in migration and proliferation in a variety of cancer cells, including pancreatic cancer cells, in vitro. In the current study, we examined whether an orally active LPA antagonist is effective for pancreatic cancer tumorigenesis and metastasis in vivo. Oral administration of Ki16198, which is effective for LPA(1) and LPA(3), into YAPC-PD pancreatic cancer cell-inoculated nude mice significantly inhibited tumor weight and remarkably attenuated invasion and metastasis to lung, liver, and brain, in association with inhibition of matrix metalloproteinase (MMP) accumulation in ascites in vivo. Ki16198 inhibited LPA-induced migration and invasion in several pancreatic cancer cells in vitro, which was associated with the inhibition of LPA-induced MMP production. In conclusion, Ki16198 is a promising orally active LPA antagonist for inhibiting the invasion and metastasis of pancreatic cancer cells. The inhibitory effects of the antagonist on invasion and metastasis in vivo may be partially explained by the inhibition of motility activity and MMP production in cancer cells.
authors.affiliation: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Komachi
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tobo
authors.forename: Chihiro
authors.initials: C
authors.lastname: Mogi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamada
authors.forename: Hideo
authors.initials: H
authors.lastname: Ohta
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tomura
authors.forename: Takao
authors.initials: T
authors.lastname: Kimura
authors.forename: Dong-Soon
authors.initials: DS
authors.lastname: Im
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yanagida
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishii
authors.forename: Izumi
authors.initials: I
authors.lastname: Takeyoshi
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Okajima
mesh_terms: D000818:Animals; D001201:Ascites / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008246:Lysophospholipids / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C574551:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonylamino)-3-methyl-5-isoxazolyl)benzylsulfanyl)propanoic acid methyl ester; D007555:Isoxazoles; D008246:Lysophospholipids; D061965:Matrix Metalloproteinase Inhibitors; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C032881:lysophosphatidic acid