Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The saponin digitonin, the aglycone digitoxigenin and five cardiac glycosides were evaluated for cytotoxicity using primary cultures of tumor cells from patients and a human cell line panel (representing different cytotoxic drug-resistance patterns). Of these seven compounds, proscillaridin A was the most potent (IC(50): 6.4--76 nM), followed by digitoxin, and then ouabain, digoxin, lanatoside C, digitoxigenin and digitonin. Correlation analysis of the log IC(50) values for the cell lines in the panel showed that compound cytotoxicity was only slightly influenced by resistance mechanisms that involved P-glycoprotein, topoisomerase II, multidrug resistance-associated protein and glutathione-mediated drug resistance. Digitoxin and digoxin expressed selective toxicity against solid tumor cells from patients, while proscillaridin A expressed no selective toxicity against either solid or hematological tumor cells. The results revealed marked differences in cytotoxicity between the cardiac glycosides, both in potency and selectivity, and modes of action for cytotoxicity that differ from that of commonly used anticancer drugs.
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PMID:Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. 1139 76

Digitoxin is used in the treatment of cardiac congestion and some types of cardiac arrhythmias. The mechanism of action of this cardiac glycoside suggested that it might antagonize the anticancer activity of topoisomerase II poisons. The present report shows that digitoxin, at concentrations commonly found in the plasma of cardiac patients, significantly reduced etoposide and idarubicin-induced topoisomerase II cleavable complexes in K562 leukemia cells. This may lead to a reduction in the anticancer effect of these two topoisomerase II poisons when they are used in the clinic concurrently with digitoxin.
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PMID:Digitoxin, at concentrations commonly found in the plasma of cardiac patients, antagonizes etoposide and idarubicin activity in K562 leukemia cells. 1638 58

The well known and accepted mode of action of cardiac glycosides is inhibition of the ubiquitous plasma membrane Na+, K+-ATPase that leads to increased intracellular Ca2+ ion concentrations. Ca2+ ions play pivotal role in many signaling pathways including those regulating apoptosis. It has been suggested that some forms of cardiac glycosides inhibit proliferation and induce apoptosis in prostate cancer cells in clinically relevant concentrations. It was also found out that the degree to which cardiac glycosides inhibited cancer cell growth was correlated to topoisomerase II-inhibiting activity. Digitoxin at concentrations found in cardiac patients induced levels of DNA-topoisomerase II cleavable complexes similar to etoposide, a topoisomerase II poison widely used in cancer chemotherapy. Cardiac glycosides can also regulate one of the most potent angiogenesis promoting substances, fibroblast growth factor-2 (FGF-2), and may inhibit activation of the transcription factor NF-kappaB. FGF-2 and NF-kappaB are relevant targets for anticancer drugs. There is growing interest in evaluating the oleander products and possibly other cardiac glycosides as antineoplastic agents. The first of these therapies to be developed in the United States is a patented, water-soluble oleander extract called Anvirzel.
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PMID:Cardiac glycosides in cancer research and cancer therapy. 1751 73