Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel small molecule inhibitor, 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB), competes with the Bak BH3 peptide to bind Bcl-2 protein with a binding affinity of IC(50) = 0.70 microM, as assessed by a fluorescence polarization based binding assay. HL-60 cells express the highest levels of Bcl-2 among the cell lines examined. Treated with 5 microM of MNB only for 6 h, 85% of HL-60 cells were detected to undergo apoptosis. Pan-caspase inhibitor, Z-VAD-FMK, blocks MNB-induced apoptosis in HL-60 cells. Caspase-2, caspase-3, caspase-7, caspase-8, caspase-9, and PARP activation were observed at as early as 4 to 6 h of MNB treatment. In addition, it has been confirmed that the caspase-3 specific inhibitor, Z-DEVD-FMK, blocks the activation of caspase-8 in MNB-treated HL-60 cells. MNB treatment does not change Bcl-2 or Bax expression level in HL-60 cells, but causes Bid cleavage. Further experiments have illustrated that MNB inhibits the heterodimerization of Bcl-2 with Bax or Bid, reduces the mitochondrial membrane potential (DeltaPsimt), and induces cytochrome c release from mitochondria in HL-60 cells. These results suggest that MNB induces apoptosis in HL-60 by inhibiting the heterodimerization of Bcl-2 with pro-apoptosis Bcl-2 members, resulting in a decrease in the mitochondrial membrane potential and cytochrome c release, activation of caspases and PARP; it is a caspase-dependent process in which the activation of caspase-8 is dependent on the mitochondrial apoptosis signal transduction pathway. MNB prolongs the life spans of HL-60 bearing mice, potently kills fresh AML and ALL cells, indicating that it has the potential to be developed to treat leukemia.
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PMID:A novel Bcl-2 small molecule inhibitor 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB)-induced apoptosis in leukemia cells. 1739 62

Tetra-O-methyl nordihydroguaiaretic acid (M4N) was shown to induce G2 arrest and suppress human xenograft tumor growth by inhibiting Cdc2 and survivin. We examined the effect of M4N on leukemia and found that M4N inhibited growth and induced cell death in leukemic cell lines and blasts from AML patients. However, no significant changes in Cdc2 and survivin levels and G2 arrest were observed. Cell death and growth inhibition were dependent neither on XIAP, Bcl-2, and Bcl-X(L) levels nor on caspase-8. M4N did not promote cell differentiation in HL-60 cells. Interestingly, significant inhibition of AKT phosphorylation was observed in M4N treated OCI-AML3 cells. Collectively, our data showed that M4N inhibited cell growth and induced cell death in both leukemic cell lines and AML patient sample via a mechanism not mediated by Cdc2 and survivin inhibition and suggested that the extrinsic and the mitochondrial apoptotic pathways are not essential.
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PMID:Tetra-O-methyl nordihydroguaiaretic acid inhibits growth and induces death of leukemia cells independent of Cdc2 and survivin. 1745 37

The synthetic triterpenoid CDDO-Im-induced apoptosis of patient-derived AML blasts: 11/25 AMLs were highly sensitive, while the remaining were moderately sensitive to CDDO-Im. The addition of TRAIL significantly potentiated the cytotoxic effect of CDDO-Im, through mechanisms involving the induction of TRAIL-R1/TRAIL-R2 and downmodulation of TRAIL-R3/TRAIL-R4. Biochemical studies showed that CDDO-Im: induced a rapid and marked GSH depletion and antioxidants (GSH or NAC) completely inhibited its pro-apoptotic effect; sequentially activated caspase-8, -9 and -3; caspase inhibitors partially protected AML blasts from CDDO-Im-induced apoptosis; resistance of AML blasts to CDDO-Im-induced apoptosis correlated with low caspase-8/FADD and high Bcl-X(L) expression in leukemic blasts.
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PMID:Resistance of acute myeloid leukemic cells to the triterpenoid CDDO-Imidazolide is associated with low caspase-8 and FADD levels. 1830 28

Kinesin spindle protein (KSP), a microtubule-associated motor protein essential for cell cycle progression, is overexpressed in many cancers and is a potential anti-tumor target. We found that inhibition of KSP by a selective inhibitor, ARRY-520, blocked cell cycle progression, leading to apoptosis in acute myeloid leukemia cell lines that express high levels of KSP. Knockdown of p53, overexpression of XIAP and mutation in caspase-8 did not significantly affect sensitivity to ARRY-520, suggesting that the response is independent of p53, XIAP and the extrinsic apoptotic pathway. Although ARRY-520 induced mitotic arrest in both HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, cell death was blunted in HL-60Bcl-2 cells, suggesting that the apoptotic program is executed through the mitochondrial pathway. Accordingly, inhibition of Bcl-2 by ABT-737 was synergistic with ARRY-520 in HL-60Bcl-2 cells. Furthermore, ARRY-520 increased Bim protein levels prior to caspase activation in HL-60 cells. ARRY-520 significantly inhibited tumor growth of xenografts in SCID mice and inhibited AML blast but not normal colony formation, supporting a critical role for KSP in proliferation of leukemic progenitor cells. These results demonstrate that ARRY-520 potently induces cell cycle block and subsequent death in leukemic cells via the mitochondrial pathway and has the potential to eradicate AML progenitor cells.
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PMID:Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells. 1945 29

Aqueous Viscum album L. extracts are widely used in complementary cancer medicine. Hydrophobic triterpene acids also possess anti-cancer properties, but due to their low solubility they do not occur in significant amounts in aqueous extracts. Using cyclodextrins we solubilised mistletoe triterpenes (mainly oleanolic acid) and investigated the effect of a mistletoe whole plant extract on human acute myeloid leukaemia cells in vitro, ex vivo and in vivo. Single Viscum album L. extracts containing only solubilised triterpene acids (TT) or lectins (viscum) inhibited cell proliferation and induced apoptosis in a dose-dependent manner in vitro and ex vivo. The combination of viscum and TT extracts (viscumTT) enhanced the induction of apoptosis synergistically. The experiments demonstrated that all three extracts are able to induce apoptosis via caspase-8 and -9 dependent pathways with down-regulation of members of the inhibitor of apoptosis and Bcl-2 families of proteins. Finally, the acute myeloid leukaemia mouse model experiment confirmed the therapeutic effectiveness of viscumTT-treatment resulting in significant tumour weight reduction, comparable to the effect in cytarabine-treated mice. These results suggest that the combination viscumTT may have a potential therapeutic value for the treatment AML.
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PMID:A Natural Combination Extract of Viscum album L. Containing Both Triterpene Acids and Lectins Is Highly Effective against AML In Vivo. 2624 18

Baicalin is a flavonoid compound isolated from Scutellaria baicalensis, a Chinese traditional medicinal herb, and is used as an anti-inflammatory, antibacterial, anxiolytic and hepatoprotective drug. Accumulating evidence has demonstrated that baicalin exhibits potent antitumor properties by suppressing cell growth, arresting cell cycle progression and inducing differentiation or apoptosis in leukemia cell lines. However, whether or not the extrinsic pathway is involved in baicalin-induced apoptosis of leukemia cells and the mechanisms underlying the antitumor activity of baicalin remain unclear. In the present study, the effect of baicalin on the expression of caspase-8, Fas cell surface death receptor (Fas) and Fas ligand in HL-60 cells was assessed, and it was demonstrated that the Fas-mediated extrinsic pathway was also involved in baicalin-triggered cell apoptosis, in addition to the intrinsic pathway. Furthermore, baicalin was able to inhibit the proliferation of HL-60 cells by arresting the cell cycle at the G0/G1 phase, and by down-regulating Myc proto-oncogene protein (c-Myc) along with its target gene, human telomerase reverse transcriptase. In summary, the results of the present study demonstrated that baicalin was able to inhibit the growth of HL-60 cells through blockade of the G0/G1 phase of the cell cycle, and significantly induce the apoptosis of cells by activating the intrinsic and extrinsic pathways. The inhibition of HL-60 cell growth was also demonstrated to be mediated by telomerase inhibition through suppression of c-Myc. The results of the present study highlight the possibility of baicalin as a promising regimen for the treatment of AML.
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PMID:The downregulation of c-Myc and its target gene hTERT is associated with the antiproliferative effects of baicalin on HL-60 cells. 2916 3

Caspase-8 is an initiator of apoptotic signalling, and aberrations in procaspase-8 have been verified to be associated with malignant tumours. In previous studies, various procaspase-8 mutants were identified in AML patients, such as Q482H and M476W/Q482H mutations. The Q482H mutation can abolish caspase-8-mediated apoptosis by attenuating the dimerization of procaspase-8 protein monomers, causing AML patients carrying the Q482H mutation to develop resistance to chemotherapeutics. The patients with the M476W/Q482H mutation were sensitive to chemotherapy. Nevertheless, the underlying molecular mechanism is still unclear in regard to how the M476W/Q482H mutation restored caspase-8-mediated apoptosis. In this study, apoptosis was detected in the cells overexpressing the WT or mutant procaspase-8 with or without TRAIL treatment. Western blotting was devoted to detect the cleavage of procaspase-8 or the expression of proteins downstream in the apoptotic cascade and CO-IP was employed to analyze the dimerization of WT and mutant procaspase-8 proteins. Results demonstrated cells carrying the M476W/Q482H mutation restored caspase-8-mediated and TRAIL-induced apoptosis. The M476W/Q482H mutation recovered the dimerization of procaspase-8. Taken together, the M476W/Q482H mutation have restored caspase-8-mediated apoptosis resulting from the recovery of procaspase-8 dimerization.
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PMID:The M476W/Q482H mutation of procaspase-8 restored caspase-8-mediated apoptosis. 3107 61