Inhibition of Histone Deacetylase Class I but not Class II Is Critical for the Sensitization of Leukemic Cells to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis

2007 ◽  
Vol 2007 ◽  
pp. 146-147
Author(s):  
M.S. Gordon
Keyword(s):  
Tumor Necrosis Factor ◽  
Histone Deacetylase ◽  
Tumor Necrosis ◽  
Class Ii ◽  
Class I ◽  
Leukemic Cells ◽  
Induced Apoptosis ◽  
Necrosis Factor

Thioridazine Enhances TRAIL Cytotoxicity in Human Myeloid Leukemic Cells By up-Regulating DR5 and Modulating PI3K-AKT-NF-Kb Pathway

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4938-4938
Author(s):  
Yi Wang ◽  
Yangyi Bao ◽  
Leiming Xia ◽  
Liu Liu ◽  
Kunyuan Guo ◽  
...  
Keyword(s):  
Cancer Research ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Down Regulation ◽  
Trail Receptors ◽  
Trail Resistance ◽  
Induced Apoptosis ◽  
Necrosis Factor

Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in cancer cells but not in most normal cells, and is identified to be effective in various cancers, include myeloid leukemic cells[1]. Although some leukemia cell lines, K562 and KG-1, are sensitive to TRAIL, many showed certain degrees of resistance to TRAIL-mediated apoptosis[2,3], and the mechanism remains largely unknown, which forced us to find out ways to solve the problem. In this study, we investigated whether thioridazine, a phenothiazine derivative, could overcome the TRAIL resistance in K562 and KG-1 cells. Recently, we showed that Compared to treatment with thioridazine or TRAIL alone, co-treatment with thioridazine and TRAIL-induced apoptosis in K562 and KG-1 cells synergistically. This combination led to activation of caspase-8 and Bid, the cytosolic cumulation of cytochrome c from mitochondria as well as caspase-3 activated downstream. Treatment with thioridazine induced down-regulation of PI3K-AKT-NF-κB pathway. meanwhile, thioridazine dropped the level of NF-κB-dependent Bcl-xL, leading caspase activated and Bid cleaved. the expression of TRAIL-receptors in both K562 and KG-1 cells underwentthe treatment of thioridazine investigated that thioridazine significantly up-regulated DR5 by up to 51.22%, but not other TRAIL-receptors such as DR4, decoy receptor 1, and DcR2. Therefore, our results indicate that the combination of TRAIL with thioridazine overturn TRAIL resistance through Up-regulating the expression of DR5 and down-regulation of AKT protein, and combination treatment with thioridazine and TRAIL may be a novel therapeutic strategy in leukemia. Reference: Srivastava R K. TRAIL/Apo-2L: mechanisms and clinical applications in cancer.[J]. Neoplasia, 2001, 3(6):535-546. Nimmanapalli R, Porosnicu M, Nguyen D, et al. Cotreatment with STI-571 enhances tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL or apo-2L)-induced apoptosis of Bcr-Abl-positive human acute leukemia cells.[J]. Clinical Cancer Research An Official Journal of the American Association for Cancer Research, 2001, 7(2):350-357. Yang T, Lan J, Huang Q, et al. Embelin sensitizes acute myeloid leukemia cells to TRAIL through XIAP inhibition and NF-κB inactivation.[J]. Cell Biochemistry & Biophysics, 2015, 71(1):291-297. Disclosures No relevant conflicts of interest to declare.

scholarly journals Macrophage-dependent Apoptosis of CD4+ T Lymphocytes from HIV-infected Individuals Is Mediated by FasL and Tumor Necrosis Factor

1997 ◽  
Vol 185 (1) ◽  
pp. 55-64 ◽  
Author(s):  
Andrew D. Badley ◽  
David Dockrell ◽  
Margaret Simpson ◽  
Ron Schut ◽  
David H. Lynch ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Tumor Necrosis ◽  
Human Macrophages ◽  
Infected Cells ◽  
Induced Apoptosis ◽  
Antigen Presenting ◽  
Necrosis Factor

Apoptosis of bystander uninfected CD4+ T lymphocytes by neighboring HIV-infected cells is observed in cell culture and in lymphoid tissue of HIV-infected individuals. This study addresses whether antigen-presenting cells such as human macrophages mediate apoptosis of CD4+ T cells from HIV-infected individuals. Uninfected human macrophages, and to a larger degree, HIV-infected macrophages mediate apoptosis of T cells from HIV-infected, but not from uninfected control individuals. This macrophage-dependent killing targets CD4+, but not CD8+ T lymphocytes from HIV-infected individuals, and direct contact between macrophages and lymphocytes is required. Additional analyses indicated that the apoptosis-inducing ligands, FasL and tumor necrosis factor (TNF), mediate this macrophage-induced apoptosis of CD4+ T cells. These results support a role for macrophage-associated FasL and TNF in the selective depletion of CD4+ T cells in HIV-infected individuals.

scholarly journals Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

2004 ◽  
Vol 15 (7) ◽  
pp. 3266-3284 ◽  
Author(s):  
Romaine Ingrid Fernando ◽  
Jay Wimalasena
Keyword(s):  
Breast Cancer ◽  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Dominant Negative ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

Estrogens such as 17-β estradiol (E2) play a critical role in sporadic breast cancer progression and decrease apoptosis in breast cancer cells. Our studies using estrogen receptor-positive MCF7 cells show that E2 abrogates apoptosis possibly through phosphorylation/inactivation of the proapoptotic protein BAD, which was rapidly phosphorylated at S112 and S136. Inhibition of BAD protein expression with specific antisense oligonucleotides reduced the effectiveness of tumor necrosis factor-α, H2O2, and serum starvation in causing apoptosis. Furthermore, the ability of E2 to prevent tumor necrosis factor-α-induced apoptosis was blocked by overexpression of the BAD S112A/S136A mutant but not the wild-type BAD. BAD S112A/S136A, which lacks phosphorylation sites for p90RSK1 and Akt, was not phosphorylated in response to E2 in vitro. E2 treatment rapidly activated phosphatidylinositol 3-kinase (PI-3K)/Akt and p90RSK1 to an extent similar to insulin-like growth factor-1 treatment. In agreement with p90RSK1 activation, E2 also rapidly activated extracellular signal-regulated kinase, and this activity was down-regulated by chemical and biological inhibition of PI-3K suggestive of cross talk between signaling pathways responding to E2. Dominant negative Ras blocked E2-induced BAD phosphorylation and the Raf-activator RasV12T35S induced BAD phosphorylation as well as enhanced E2-induced phosphorylation at S112. Chemical inhibition of PI-3K and mitogen-activated protein kinase kinase 1 inhibited E2-induced BAD phosphorylation at S112 and S136 and expression of dominant negative Ras-induced apoptosis in proliferating cells. Together, these data demonstrate a new nongenomic mechanism by which E2 prevents apoptosis.

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