melphalan and 7-hydroxystaurosporine

melphalan has been researched along with 7-hydroxystaurosporine* in 1 studies

Other Studies

1 other study(ies) available for melphalan and 7-hydroxystaurosporine

Article	Year
Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6-independent mechanism. Blood, 2002, Nov-01, Volume: 100, Issue:9 The effects of combined exposure to the checkpoint abrogator UCN-01 and pharmacologic MEK1/2 inhibitors were examined in human multiple myeloma (MM) cell lines. Treatment of RPMI8226, NCI-H929, and U266 MM cells with a minimally toxic concentration of UCN-01 (150 nM) for 24 hours resulted in mitogen-activated protein (MAP) kinase activation, an effect that was blocked by coadministration of the MEK1/2 inhibitor PD184352. These events were accompanied by enhanced activation of p34(cdc2) and a marked increase in mitochondrial damage (loss of DeltaPsim; cytochrome c and Smac/DIABLO (direct IAP binding protein with low pI) release), poly(ADP-ribose) polymerase (PARP) cleavage, and apoptosis. PD184352/UCN-01 also dramatically reduced clonogenic survival in each of the MM cell lines. In contrast to As(2)0(3), apoptosis induced by PD184352/UCN-01 was not blocked by the free-radical scavenger N-acetyl-L-cysteine. Whereas exogenous interleukin 6 substantially prevented dexamethasone-induced lethality in MM cells, it was unable to protect them from PD184352/UCN-01-induced apoptosis despite enhancing Akt activation. Insulinlike growth factor 1 (IGF-1) also failed to diminish apoptosis induced by this drug regimen. MM cell lines selected for a high degree of resistance to doxorubicin, melphalan, or dexamethasone, or displaying resistance secondary to fibronectin-mediated adherence, remained fully sensitive to PD184352/UCN-01-induced cell death. Finally, primary CD138(+) MM cells were also susceptible to UCN-01/MEK inhibitor-mediated apoptosis. Together, these findings suggest that simultaneous disruption of cell cycle and MEK/MAP kinase signaling pathways provides a potent stimulus for mitochondrial damage and apoptosis in MM cells, and also indicate that this strategy bypasses the block to cell death conferred by several other well-described resistance mechanisms. Topics: Alkaloids; Apoptosis; Benzamides; Bone Marrow Cells; CDC2 Protein Kinase; Cell Adhesion; Cell Cycle; Dexamethasone; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Activation; Enzyme Inhibitors; Free Radical Scavengers; Humans; Insulin-Like Growth Factor I; Interleukin-6; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Melphalan; Membrane Glycoproteins; Mitochondria; Mitogen-Activated Protein Kinase Kinases; Multiple Myeloma; Neoplasm Proteins; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proteoglycans; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Staurosporine; Syndecan-1; Syndecans; Tumor Cells, Cultured; Tumor Stem Cell Assay	2002

Article

Year

Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6-independent mechanism.

Blood, 2002, Nov-01, Volume: 100, Issue:9

The effects of combined exposure to the checkpoint abrogator UCN-01 and pharmacologic MEK1/2 inhibitors were examined in human multiple myeloma (MM) cell lines. Treatment of RPMI8226, NCI-H929, and U266 MM cells with a minimally toxic concentration of UCN-01 (150 nM) for 24 hours resulted in mitogen-activated protein (MAP) kinase activation, an effect that was blocked by coadministration of the MEK1/2 inhibitor PD184352. These events were accompanied by enhanced activation of p34(cdc2) and a marked increase in mitochondrial damage (loss of DeltaPsim; cytochrome c and Smac/DIABLO (direct IAP binding protein with low pI) release), poly(ADP-ribose) polymerase (PARP) cleavage, and apoptosis. PD184352/UCN-01 also dramatically reduced clonogenic survival in each of the MM cell lines. In contrast to As(2)0(3), apoptosis induced by PD184352/UCN-01 was not blocked by the free-radical scavenger N-acetyl-L-cysteine. Whereas exogenous interleukin 6 substantially prevented dexamethasone-induced lethality in MM cells, it was unable to protect them from PD184352/UCN-01-induced apoptosis despite enhancing Akt activation. Insulinlike growth factor 1 (IGF-1) also failed to diminish apoptosis induced by this drug regimen. MM cell lines selected for a high degree of resistance to doxorubicin, melphalan, or dexamethasone, or displaying resistance secondary to fibronectin-mediated adherence, remained fully sensitive to PD184352/UCN-01-induced cell death. Finally, primary CD138(+) MM cells were also susceptible to UCN-01/MEK inhibitor-mediated apoptosis. Together, these findings suggest that simultaneous disruption of cell cycle and MEK/MAP kinase signaling pathways provides a potent stimulus for mitochondrial damage and apoptosis in MM cells, and also indicate that this strategy bypasses the block to cell death conferred by several other well-described resistance mechanisms.

Topics: Alkaloids; Apoptosis; Benzamides; Bone Marrow Cells; CDC2 Protein Kinase; Cell Adhesion; Cell Cycle; Dexamethasone; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Activation; Enzyme Inhibitors; Free Radical Scavengers; Humans; Insulin-Like Growth Factor I; Interleukin-6; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Melphalan; Membrane Glycoproteins; Mitochondria; Mitogen-Activated Protein Kinase Kinases; Multiple Myeloma; Neoplasm Proteins; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proteoglycans; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Staurosporine; Syndecan-1; Syndecans; Tumor Cells, Cultured; Tumor Stem Cell Assay

2002