Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and its use in reducing osteoporosis and cancer-induced osteolysis is increasing. Recent findings indicated that ZOL has a direct effect on cancer cells. In this study, the effect of ZOL was examined on the aggressive MDA-MB-231 breast cancer cell line. ZOL induces an important inhibition of cell invasion at low concentrations (1 microM). This is not explained by modifications of proteases involved in cell invasiveness (matrix metalloproteinases and urokinase-type plasminogen activator), but by a disorganisation of actin cytoskeleton due to RhoA inhibition related to its defective prenylation as it was reversed by geranylgeraniol (GGOH) and mimicked by the Rho selective inhibitor C3 exoenzyme. In addition, ZOL inhibits the chemotactic effect induced by stromal cell-derived factor 1(SDF-1), a chemokine greatly involved in cancer metastasis to bone. This effect is related to both reduction of cell motility induced by RhoA inhibition and to a decreased expression of CXCR-4, the SDF-1 receptor. Finally, ZOL reduces Cox-2 expression and, consequently, the secretion of prostaglandins E2 (PGE2) in a RhoA-independent manner. This inhibition could contribute to bone protection in breast cancers because PGE2 stimulates osteoclast-mediated bone resorption. In summary, new insights in the mechanism of ZOL action on aggressive breast cancer cells are demonstrated and could explain its beneficial action in both the reduction of osteolysis and prevention of metastasis.
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PMID:New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects. 1277 33

Beside their use as antiresorptive drug, bisphosphonates are well known to stimulate gammadelta T cells and to have direct effects on tumor growth. We determined the direct cytotoxic potential, induction of apoptosis, and antimigratory effect of zoledronic acid. The susceptibility of pancreatic carcinoma cells pretreated with bisphosphonates against gammadelta T cells was tested and the subgroup involved in killing was determined. Zoledronic acid has a cytotoxic potential even at pharmacologic dosage. Zoledronic acid does not only induce apoptosis by inhibiting the Ras-pathway but has also an antimetastatic effect as shown in migration assays and by down-regulation of urokinase plasminogen activator. Freshly prepared gammadelta T cells consisting mainly of Vdelta2 cells showed increased cytotoxicity against bisphosphonate-treated pancreatic carcinoma cells. Our results demonstrate that zoledronic acid has a direct apoptotic effect on pancreatic carcinoma cells and has antimigratory properties. Tumor cells treated with zoledronic acid are more vulnerable against Vgamma9 Vdelta2 T cell attack. Treatment with zoledronic acid for patients with pancreatic carcinoma might be an option.
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PMID:Zoledronic acid has direct antiproliferative and antimetastatic effect on pancreatic carcinoma cells and acts as an antigen for delta2 gamma/delta T cells. 1745 12