WF-536 inhibits metastatic invasion by enhancing the host cell barrier and inhibiting tumour cell motility.
1. Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) is involved in the development of tumour metastasis. Wf-536, (+)-(R)-4-(1-Aminoethyl)-N-(4-pyridyl) benzamide monohydrochloride, a novel inhibitor of ROCK, inhibits tumour metastasis in some animal models. To metastasise, tumour cells have to disturb the tight intercellular junctions and the basement membrane matrix of the host tissue, which, respectively, create an intercellular barrier and the extracellular membrane. To clarify the mechanism of Wf-536 in inhibition of tumour metastasis, we analysed the effect of Wf-536 on the transition of tumour cells through the host cell layer and the basement membrane in in vitro systems. 2. In a coculture system of human fibrosarcoma HT1080 cells plated on a monolayer of human ECV304 cells, Wf-536 (0.3-3 micromol/L) inhibited the paracellular infiltration of tumour cells. 3. Wf-536 (3-30 micromol/L) inhibited the invasion of tumour cells through the reconstituted basement membrane (Matrigel) layer. 4. Wf-536 (10-30 micromol/L) inhibited the migration of tumour cells. At 0.3-3 micromol/L, Wf-536 also restrained hepatocyte growth factor/scatter factor (HGF)-induced increases in paracellular permeability of the ECV304 cell layer. 5. These results suggest that Wf-536 suppresses tumour metastasis by both enhancing the barrier function of host cell layers and inhibiting tumour cell motility at the stage of host tissue penetration by metastatic tumour cells.
Nakajima
Masahide
M
Pharmaceuticals Research Unit, Mitsubishi Pharma Corporation, Kanagawa, Japan. Nakajima.Masahide@mh.m-pharma.co.jp
Katayama
Ken-Ichi
K
Tamechika
Ichiro
I
Hayashi
Kazutaka
K
Amano
Yusaku
Y
Uehata
Masayoshi
M
Goto
Nobuharu
N
Kondo
Takao
T
D001485:Basement Membrane / Q000187:drug effects / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D018920:Coculture Techniques / Q000379:methods; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D019108:Tight Junctions / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured; D054460:rho-Associated Kinases
D001549:Benzamides; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C460080:Y 32885; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases