Bisphosphonates inhibit stromelysin-1 (MMP-3), matrix metalloelastase (MMP-12), collagenase-3 (MMP-13) and enamelysin (MMP-20), but not urokinase-type plasminogen activator, and diminish invasion and migration of human malignant and endothelial cell lines.
Bisphosphonates (clodronate, alendronate, pamidronate and zoledronate) at therapeutically attainable non-cytotoxic concentrations inhibited MMP-3, -12, -13 and -20 as well as MMP-1, -2, -8 and -9, but not urokinase-type plasminogen activator (uPA), a serine proteinase and a pro-MMP activator. Dose-dependent inhibition was shown by three independent MMP assays. The inhibition was reduced in the presence of an increased concentration of Ca(2+) when compared to physiologic Ca(2+) concentration. Alendronate inhibited the in vitro invasion (Matrigel) of human HT1080 fibrosarcoma and C8161 melanoma cells, and the random migration of these malignant and endothelial cell lines capable of expressing MMPs and uPA. The concentration of alendronate required to inhibit 50% of the activity (IC(50)=40-70 microM) of MMPs corresponded to the IC(50) of down-regulation of in vitro invasion and migration. The ability of bisphosphonates to down-regulate the in vitro invasion and random migration was comparable or slightly better in relation to the selective gelatinase inhibitor CTTHWGFTLC peptide. Alendronate but not CTTHWGFTLC peptide promoted the adhesion of HT1080 fibrosarcoma and C8161 melanoma cell lines on fibronectin. Bisphosphonates are broad-spectrum MMP inhibitors and this inhibition involves cation chelation. Bisphosphonates further exert antimetastatic, anti-invasive and cell adhesion-promoting properties, which may prevent metastases not only into hard tissues but also to soft tissues.
Heikkilä
Pia
P
Laboratory Diagnostics, Department of Medicine, Biomedicum and Oral Medicine, Helsinki University Central Hospital and ORTON Research Institute, Invalid Foundation, Helsinki, Finland. pia.heikkila@helsinki.fi
Teronen
Olli
O
Moilanen
Merja
M
Konttinen
Yrjö T
YT
Hanemaaijer
Roeland
R
Laitinen
Minna
M
Maisi
Päivi
P
van der Pluijm
Gabri
G
Bartlett
John D
JD
Salo
Tuula
T
Sorsa
Timo
T
D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000737:chemistry / Q000378:metabolism; D053508:Matrix Metalloproteinase 12; D053509:Matrix Metalloproteinase 13; D053519:Matrix Metalloproteinase 20; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors
D004164:Diphosphonates; D004338:Drug Combinations; D005353:Fibronectins; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D014568:Urokinase-Type Plasminogen Activator; C507079:MMP13 protein, human; C507111:MMP20 protein, human; D053509:Matrix Metalloproteinase 13; D053519:Matrix Metalloproteinase 20; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12