Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activity of receptor-bound urokinase plasminogen activator (uPA) on the surface of colon cancer cells appears to be a function of the number of uPA receptors. The regulation of uPA therefore may determine the invasive phenotype. The effects of amiloride on the modulation of uPA mRNA and protein induced by phorbol ester (PMA) and cycloheximide (CHX) were studied in four colon cancer cell lines, HCT116, KM12SM, LIM1215 and LS123. Northern blot analyses showed that PMA induced uPA mRNA that peaked at 2-48 h in HCT116 cells. In all colon cancer cell lines tested, the expression of uPA mRNA by PMA was super-induced after the addition of the protein synthesis inhibitor CHX, suggesting that stimulation of uPA gene expression does not require de novo protein synthesis. uPA mRNA was also induced by CHX alone, indicating that there may be a labile protein which inhibits uPA mRNA processing. Amiloride profoundly inhibited uPA mRNA production at concentrations between 0.1-1 mM in the presence or absence of PMA or CHX. uPA protein levels on the colon cancer cell surface reflected PMA induction and amiloride inhibition of uPA mRNA levels. Transcriptional elongation experiments using isolated nuclei indicated that while the induction effects of PMA or CHX on uPA gene expression were mediated at the post-transcriptional level, amiloride acted at both transcription and post-transcription levels. The inhibitory effects of amiloride on uPA gene expression reported in this paper may offer the prospect of developing new therapeutic approaches to the prevention of invasion and metastasis by adenocarcinomas.
Clin Exp Metastasis 1995 May
PMID:Amiloride modulates urokinase gene expression at both transcription and post-transcription levels in human colon cancer cells. 775 Feb 7

Amiloride is an inhibitor of urokinase plasminogen activator (uPA), an essential component of the plasminogen/plasmin enzyme system. Inhibition of uPA prevents the conversion of plasminogen to tumor cell surface bound plasmin which is required for initiation of the metastatic process. MATB rat mammary cancer cells were introduced into the jugular venous system of 80 Fisher 344 female rats. Amiloride at high and low dosages was administered in the drinking water at the time of, prior to or several days following the tumor cell inoculation and continued daily for 10 days post inoculation. Control rats were maintained on water alone. The middle lobe of the right lung was examined microscopically for numbers of metastases. Suppression of metastases was significant at high amiloride dosages in all groups, and at low dosage when administered prior to inoculation. We conclude that amiloride suppresses induced metastases of rat mammary cancer, the effect being dose- and time-dependent.
Clin Exp Metastasis 1998 May
PMID:Time and dose dependency of the suppression of pulmonary metastases of rat mammary cancer by amiloride. 962 14

Tumor cell metastasis can be suppressed by the attenuation of proteolytic and angiogenic events that are mediated by tumor and endothelial cells. Combinations of specific inhibitors directed to separate stages of the metastatic cascade may improve the potential for adjuvant therapies. Amiloride is an effective plasminogen activator inhibitor, while celecoxib is a cylcooxygenase-2 inhibitor. In vitro invasion assays were used to assess the effect of each inhibitor on the cellular invasion of MATB rat mammary carcinoma cells. Individually, both amiloride and celecoxib impeded cellular invasion in a dose-dependent manner. Combinations consistently exerted a significant inhibitory response (91 to 99%). These inhibitors were administered alone and in combination to evaluate their efficacy in the prevention of pulmonary metastases from a primary rat mammary carcinoma. Amiloride and celecoxib, alone and in combination, consistently showed no effect on the growth of primary tumors. The combined inhibitors were able to reduce significantly the growth of local recurrences following primary tumor excision and metastatic incidence rates. Numbers of pulmonary metastases were reproducibly and significantly decreased with the administration of amiloride and celecoxib, alone and in combination. Celecoxib alone was most effective with a reduction in 98% of the metastases, yet distinctions were observed in the results with respect to the local recurrences, blood levels for the inhibitors and tissue production of prostaglandin E2. These data demonstrate the potential use for celecoxib, alone and in combination with amiloride, in the suppression of metastases.
Clin Exp Metastasis 2004
PMID:Control of pulmonary metastases of rat mammary cancer by inhibition of uPA and COX-2, singly and in combination. 1555 90