These data are consistent with ABT both increasing the sensitivity to carboplatin as well as decreasing the time at which cell death is observed.To measure the <a href="http://www.targetmol.com/compound/Glipizide">Glipizide</a>
Sensitization of ovarian cancer cells to carboplatin, cells were simultaneously treated with carboplatin and the indicated concentration of ABT. The results are representative of three experiments.B, IGROV cells were treated with the indicated concentration of carboplatin in the absence of. Columns, mean percentage of cell numbers measured in samples treated with DMSO alone; bars, SD. D, IGROV cells were treated with DMSO, ABT, or carboplatin combined with either ABT or ABTE.After h, the cells were lysed and PARP cleavage was assessed.The results are representative of three experiments.E, OVCAR or A cells were treated with carboplatin. The results are representative of three experiments.F, IGROV cells were treated with the indicated concentrations of carboplatin and either DMSO. After h, the adherent and detached cells were combined and DNA fragmentation assessed using an ELISA to measure nucleosome formation.PARP cleavage was observed in cells treated with either carboplatin or the combination of carboplatin and ABT.However, the inclusion of ABT decreased the time at which PARP cleavage was first observed and the time at which the cleavage was essentially complete. The ability of ABT to potentiate the PARP cleavage was dependent on the ABT enantiomer used.Following hof treatment with either carboplatin alone, ABT alone, or carboplatin combined with the less active enantiomer ABTE, very modest PARP cleavage was observed.In contrast, carboplatin and ABT again led to a substantial increase in PARP processing. In OVCAR cells, ABT also promoted earlier cleavage of PARP, consistent with the increase in sensitivity of this cell line to carboplatin when cells were treated with ABT. In contrast, ABT did not increase the sensitivity of A cells to carboplatin. To substantiate these observations using an alternative measure of apoptosis, DNA fragmentation was measured using an ELISA which detects nucleosome formation.However, the combination of ABT with carboplatin led to an ffold increase in nucleosome formation. BclXL siRNA also sensitizes ovarian cancer cells to carboplatin.In OVCAR cells, in which ABT caused very modest sensitization to carboplatin, both siRNA had a modest effect on sensitivity to carboplatin. These siRNA had no measurable effect on sensitivity to carboplatin.When tested as a single agent, ABT was previously shown to potently inhibit the survival of certain cell types, whereas other cells are less sensitive.In <a href="https://www.ncbi.nlm.nih.gov/pubmed/11078468">Glipizide</a>
particular, it has been reported that expression of MCL, which is not potently inhibited by ABT, could antagonize cell death induced by ABT. Sensitization of primary cultures of cells derived from patients with ovarian cancer.More than of the cells expressed cytokeratin or epithelial antigen and adopted a cobblestone morphology in culture, suggesting that the cells were of epithelial origin.Similar to the established cell lines, these cells were only modestly sensitive to ABT. However, the sensitivity of one of these cultures to carboplatin was increased almost fold by cotreatment with carboplatin.Prior to determining whether these observations could be extended to a xenograft model in vivo, we investigated how to schedule the administration of ABT with carboplatin.