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)

Hematopoietic cytokines play crucial roles in regulation of cell cycle progression and apoptosis of hematopoietic cells. However, the effects of cytokines on cellular responses to chemotherapeutic agents and the mechanisms involved have remained elusive. Here we report that erythropoietin or IL-3 promotes G2/M arrest and prevents apoptosis induced by the topoisomerase II inhibitor etoposide in murine hematopoietic 32D cells and human leukemic UT7 cells. Erythropoietin or IL-3 significantly enhanced etoposide-induced activation-specific phosphorylation of Chk1, a checkpoint kinase that inhibits Cdc2 activation by Cdc25 phosphatases, and led to the inhibition of Cdc2 kinase activity with the persistent inhibitory phosphorylation on Tyr15. The inhibitory Cdc2 phosphorylation and G2/M block by etoposide were enhanced or inhibited by overexpression of Chk1 or by the specific Chk1 inhibitor SB218078, respectively. The G2/M arrest induced by etoposide was also enhanced or inhibited by expression of a constitutively activated or dominant-negative Akt mutant, respectively. Furthermore, SB216763 or LiCl, a specific inhibitor for the GSK3 kinase inhibited by Akt, enhanced the Chk1 phosphorylation and G2/M arrest by etoposide. These results indicate that hematopoietic cytokines protect etoposide-treated cells from DNA damage-induced apoptosis by promoting, through the PI3K/Akt/GSK3 signaling pathway, G2/M checkpoint that is dependent on Chk1-mediated inhibition of Cdc2.
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PMID:Hematopoietic cytokines enhance Chk1-dependent G2/M checkpoint activation by etoposide through the Akt/GSK3 pathway to inhibit apoptosis. 1567 26

We report the synthesis and biological evaluation of new oxophenylarcyriaflavins designed as potential anticancer agents. An efficient synthesis involving palladium-catalyzed Suzuki and Stille reactions is presented, without any indolic protective group. The central ring closure of the scaffold was performed through an electrophilic reaction on the position C-2 of the indole ring. The use of indole and 5-benzyloxyindole, along with substituted phenyl rings, generated three different scaffolds, which were successively exploited to modulate the structure. The cytotoxicity of the newly designed compounds on four cancer cell lines and activities against three kinases (CDK1, CDK5 and GSK3) were evaluated. Several compounds showed a marked cytotoxicity with IC(50) values in the sub-micromolar range, and induced important cell cycle perturbations, with a G2/M arrest. Some compounds revealed DNA binding properties and were found to inhibit topoisomerase-mediated DNA relaxation of supercoiled DNA, but these properties are not mandatory for a cytotoxic action. A novel lead compound () has been identified and warrants further investigations.
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PMID:Synthesis and biological evaluation of novel oxophenylarcyriaflavins as potential anticancer agents. 1852 73

Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (TKIs) have improved chronic myeloid leukemia (CML) patient survival markedly but fail to eradicate quiescent CML leukemia stem cells (LSCs). Thus, strategies targeting LSCs are required to induce long-term remission and achieve cure. Here, we investigated the ability of topoisomerase II (Top II) inhibitor etoposide (Eto) to target CML LSCs. Treatment with Eto combined with IM markedly induced apoptosis in primitive CML CD34+ CD38- stem cells resistant to eradication by IM alone, but not in normal hematopoietic stem cells, CML and normal mature CD34- cells, and other leukemia and lymphoma cell lines. The interaction of IM and Eto significantly inhibited phosphorylation of PDK1, AKT, GSK3, S6, and ERK proteins; increased the expression of pro-apoptotic gene Bax; and decreased the expression of anti-apoptotic gene c-Myc in CML CD34+ cells. Top II inhibitors treatment represents an attractive approach for targeting LSCs in CML patients undergoing TKIs monotherapy.
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PMID:Selective and effective targeting of chronic myeloid leukemia stem cells by topoisomerase II inhibitor etoposide in combination with imatinib mesylate in vitro. 2767 34

Notch signalling regulates neural stem cell (NSC) proliferation, differentiation and survival for the correct development and functioning of the central nervous system. Overactive Notch2 signalling has been associated with poor prognosis of aggressive brain tumours, such as glioblastoma multiforme (GBM). We recently reported that constitutive expression of the Notch2 intracellular domain (N2ICD) enhances proliferation and gliogenesis in NSCs. Here, we investigated the mechanism by which Notch2 promotes resistance to apoptosis of NSCs to cytotoxic insults. We performed ex vivo studies using NSC cultures from transgenic mice constitutively expressing N2ICD. These NSCs expressed increased levels of pro-survival factors and lack an apoptotic response to the topoisomerase inhibitor etoposide, not showing neither mitochondrial damage nor caspase activation. Interestingly, Notch2 signalling also regulated chemoresistance of human GBM cells to etoposide. We also identified a signalling crosstalk with FGF signalling pathway involved in this resistance to apoptosis of NSCs. Aberrant Notch2 expression enhances fibroblast growth factor receptor-1 (FGFR1) activity to specifically target the AKT-GSK3 signalling pathway to block apoptosis. These results have implications for understanding molecular changes involved in both tumorigenesis and therapy resistance.
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PMID:Constitutive activation of Notch2 signalling confers chemoresistance to neural stem cells via transactivation of fibroblast growth factor receptor-1. 3076 36