Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A tumor-suppressor gene, p16(INK4), which is deleted or mutated in tumors, regulates cell-cycle progression through a G(1)-S restriction point by inhibiting CDK4(CDK6)/cyclin-D-mediated phosphorylation of pRb. We have found that ectopic p16(INK4) expression increased cellular sensitivity of human non-small-cell-lung-cancer (NSCLC) A549 cells to a selective growth-inhibitory effect induced by the topoisomerase-I inhibitor 11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin (CPT-11) in vitro. In this study, we observed enhanced apoptosis characterized by DNA fragmentation in A549 cells transfected with p16(INK4) cDNA (A549/p16-1) and treated with CPT-11. This apoptosis was suppressed by the inhibitor of interleukin-1beta-converting enzyme (ICE/caspase-1) or ICE-like proteases, Z-Asp-CH2-DCB, as determined by DNA fragmentation and proteolytic cleavage of poly(ADP-ribose) polymerase, a natural substrate for CPP32/caspase-3. In A549/p16-1 cells, cytosolic peptidase activities that cleaved Z-DEVD-7-amino-4-trifluoromethylcoumarin increased during CPT-11-induced apoptosis and were suppressed by a highly specific caspase-3 and caspase-3-like inhibitor, Z-DEVD-fluoromethylketone. These findings indicate that p16(INK) is positively involved in the activation pathway of the caspase-3 induced by CPT-11. The increased delay in S-phase progression and subsequent induction of apoptosis were observed in CPT-11-treated A549/p16-1 cells on the basis of DNA histograms. Specific down-regulation of the cyclin-A protein level in A549/p16-1 cells was observed after CPT-11-treatment, whereas cyclin B, cdk2, and cdc2 protein levels were unaffected. These results suggest that ectopic p16(INK4) expression inappropriately decreases cyclin A and thereby terminates CPT-11-induced G(2)/M accumulation, which is followed by increased apoptosis in p16(INK4)-expressing A549 cells.
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PMID:Ectopic p16(ink4) expression enhances CPT-11-induced apoptosis through increased delay in S-phase progression in human non-small-cell-lung-cancer cells. 1073 46

The effect of dexrazoxane on monoclonal antibody (Mab) production by CC9C10 hybridoma cells was investigated. Dexrazoxane is a catalytic inhibitor of DNA topoisomerase II. DNA topoisomerase II has a critical role in DNA metabolism and its inhibition by dexrazoxane can prevent completion of cytokinesis. Incubation of hybridomas with dexrazoxane was found to increase specific monoclonal antibody production by up to four-fold. However, due to the growth inhibitory effects of dexrazoxane the total Mab yield decreased by 40%. Under high density culture conditions(defined here as 10(6) cells ml(-1)) specific monoclonal antibody production increased by up to 37%, which was, however, accompanied by up to a 48% decrease in Mab yield. Hybridomasthat were incubated with dexrazoxane significantly increased in size due to the inhibition of cytokinesis. Dexrazoxane was also observed to induce a delayed apoptosis in the hybridomas. The caspase inhibitor Z-VAD-fmk slightly decreased the apoptotic effects of dexrazoxane. Preincubation with the caspase inhibitorZ-Asp-CH2-DCB had no effect on dexrazoxane-treated hybridomas, but it did have antiapoptotic effects on the untreated hybridomas which normally undergo a significant basal level of apoptosis. In conclusion, dexrazoxane-induced growth inhibition (which results in higher specific antibody production) and apoptosis inhibition (which results in prolonged viability) has the potential to significantly enhance the productivity of hybridoma cell cultures.
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PMID:The effect of the catalytic topoisomerase II inhibitor dexrazoxane (ICRF-187) on CC9C10 hybridoma viability and productivity. 1900 7