Journal
ANTI-CANCER DRUGS
Volume 13, Issue 3, Pages 245-254Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00001813-200203000-00006
Keywords
bisphosphonates; inhibition; invasion; matrix metalloproteinases; migration
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Funding
- NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [R01DE014084] Funding Source: NIH RePORTER
- NIDCR NIH HHS [R01 DE014084] Funding Source: Medline
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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 Ca2+ when compared to physiologic Ca2+ 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 (IC50 = 40-70 muM) of MMPs corresponded to the IC50 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. [(C) 2002 Lippincott Williams Wilkins.].
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