Linked Life Data

8951349

Source:http://linkedlifedata.com/resource/pubmed/id/8951349

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
1997-1-3
pubmed:abstractText
Inhibitors of calcium-calmodulin-dependent processes, 1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-piperazine KN-62 and trifluoperazine (TFP), at non-cytotoxic concentrations (2 and 5 microM, respectively) enhanced etoposide (VP-16) cytotoxicity in Adriamycin-resistant (HL-60/ADR0.05) cells (3- to > 50-fold). In contrast to TFP, the inhibitor KN-62 was able to reverse resistance in HL-60/ADR0.05 cells at VP-16 concentrations that produced equivalent cytotoxicity in sensitive (HL-60/S) cells. Unlike TFP, the cellular accumulation of VP-16 in the presence of KN-62 was enhanced 1.5- to 2-fold in HL-60/S (MDR1 -ve) and HL-60/ADR0.05 (MDR1 +ve) cells. To achieve equivalent cytotoxicity, levels of VP-16 in the resistant cells were > 4-fold lower in the presence of KN-62 compared with treatment with VP-16 alone. The sensitizing effects of both KN-62 and TFP were due to enhancement (2- to 4-fold) of VP-16-induced topoisomerase II (TOPO II)-mediated DNA cleavable complex formation, and depletion of the 170 kDa (alpha) TOPO II isoform. The DNA damage induced by VP-16 in the presence of KN-62 or TFP resulted in the rapid induction of apoptosis and depletion of cells in "S" phase of the cell cycle. Both 5 microM TFP and 2 microM KN-62 enhanced the phosphorylation of 170 kDa TOPO II 1.6-fold and 1.5-fold, respectively. Results suggest that the inhibitory effect of KN-62 or TFP on calcium-calmodulin-dependent processes may be mechanistically involved in sensitizing resistant cells to VP-16 by enhancing TOPO II-mediated DNA damage.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/1-(5-Isoquinolinesulfonyl)-2-Methylp..., http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, http://linkedlifedata.com/resource/pubmed/chemical/Calcium, http://linkedlifedata.com/resource/pubmed/chemical/Calcium-Calmodulin-Dependent..., http://linkedlifedata.com/resource/pubmed/chemical/Calcium-Calmodulin-Dependent..., http://linkedlifedata.com/resource/pubmed/chemical/Calmodulin, http://linkedlifedata.com/resource/pubmed/chemical/DNA Topoisomerases, Type II, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Etoposide, http://linkedlifedata.com/resource/pubmed/chemical/KN 62, http://linkedlifedata.com/resource/pubmed/chemical/Topoisomerase II Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Trifluoperazine
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
24
pubmed:volume
52
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1903-9
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
1996
pubmed:articleTitle
Cellular events involved in the sensitization of etoposide-resistant cells by inhibitors of calcium-calmodulin-dependent processes. Role for effects on apoptosis, DNA cleavable complex, and phosphorylation.
pubmed:affiliation
Department of Cancer Biology, Cleveland Clinic Foundation, OH 44195, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.