scholarly journals Increased activity and sensitivity of mitochondrial respiratory enzymes to tumor necrosis factor alpha-mediated inhibition is associated with increased cytotoxicity in drug-resistant leukemic cell lines

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2401-2410 ◽  
Author(s):  
L Jia ◽  
SM Kelsey ◽  
MF Grahn ◽  
XR Jiang ◽  
AC Newland
Keyword(s):  
Cell Lines ◽  
Tumor Necrosis ◽  
Leukemic Cell ◽  
Drug Resistant ◽  
Necrosis Factor Alpha ◽  
Leukemic Cell Lines ◽  
Respiratory Inhibition ◽  
Factor Alpha ◽  
Necrosis Factor ◽  
Dehydrogenase Complex

The drug-resistant leukemic cell lines, CEM/VLB100 and K/DAU600, are more sensitive to tumor necrosis factor alpha (TNFalpha)-mediated cytotoxicity compared with their parental cell lines, CCRF-CEM and K562 cl.6. Drug-resistant leukemic cell lines have more active mitochondrial function, which is associated with a greater susceptibility to TNFalpha- induced respiratory inhibition. TNFalpha blocked electron transfer at three sites, NADH dehydrogenase (complex I), succinate dehydrogenase (complex II), and cytochrome c oxidase (complex IV). Respiratory rate and electron transport chain enzyme activities were significantly inhibited in the drug-resistant, TNF-sensitive cell lines. Respiratory inhibition preceded cell death by at least 5 to 8 hours. The respiratory failure was not compensated for by appropriate up- regulation of the glycolytic pathway. Increasing mitochondrial respiratory rate and enzyme activities by long-term culture with 2 mmol/L adenosine 5′-diphosphate (ADP) and Pi sensitized both drug- sensitive and drug-resistant cells to TNFalpha-induced cytolysis. Intramitochondrial free radicals generated by paraquat only had a limited and delayed effect on respiratory inhibition and cytolysis in comparison with the effect of TNFalpha. We conclude that TNFalpha- induced cytotoxicity in leukemic cells is, at least in part, mediated by inhibition of mitochondrial respiration. Free radical generation by TNFalpha may not directly lead to the observed inhibition of the mitochondrial electron transport and other mechanisms must be involved.

MLL/AF4 Positive Acute Lymphoblastic Leukemia Has Resistance to Tumor Necrosis Factor-Alpha Caused by up-Regration of S100A6

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2477-2477 ◽  
Author(s):  
Hayato Tamai ◽  
Koichi Miyake ◽  
Hiroki Yamaguchi ◽  
Masahiro Okabe ◽  
Kazuo Dan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Tumor Necrosis ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Leukemia Cell Lines ◽  
Factor Alpha ◽  
Necrosis Factor

Abstract Abstract 2477 Mixed-lineage leukemia (MLL)/AF4 positive acute lymphoblastic leukemia (ALL), which is common in infant leukemia, is associated with a poor prognosis even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The resistance to graft versus leukemia (GVL) effect may be the possible reason of the poor effect of allo-HSCT on MLL/AF4 positive ALL. Cytotoxic effector mechanisms, which are mediated by tumor necrosis factor-alpha (TNF-alpha), Fas ligand (FasL), or perforin were reported to contribute to GVL effect. We analyzed the sensitivity to TNF-alpha of MLL/AF4 positive ALL cell lines (SEM and RS4;11) together with MLL/AF4 negative leukemia cell lines (MOLT4, Raji and K562) and found that the growth inhibition by TNF-alpha of MLL/AF4 positive ALL cell lines group was significantly lower than those of another MLL/AF4 negative leukemia cell lines group (P<0.01). To examine the possible mechanism of resistance to TNF-alpha of MLL/AF4 positive leukemia, we focused on S100A6 as a possible factor, since it was reported that expression of S100A6, which is a calcium-binding protein implicated in many cellular processes and often up-regulated in cancers limits apoptosis induced by TNF-alpha through p53 inactivation in cardiac myocytes. Western Blot analysis showed that significant up-regulation of S100A6 expression and inhibition of acetyl p53/p53 expression were observed only in MLL/AF4 positive ALL cell lines in the presence of TNF-alpha (5ng/ml)(P<0.01 for S100A6 and P<0.01 for acetyl-P53/p53). To confirm the effect of S100A6 on the resistance to TNF-alpha of MLL/AF4 positive ALL cell lines, we examined the apoptosis rate of MLL/AF4 positive ALL cell lines treated with small interfering RNA (siRNA) against S100A6. TUNEL assay showed that significantly increased rate of apoptosis under s100A6 siRNA in the presence of TNF-alpha (control siRNA VS s100A6 siRNA; 42.5%&mnplus;4.5% VS 90.0%&mnplus;5.0%, P<0.01 for SEM, 32.5%&mnplus;3.5% VS 87.5%&mnplus;5.0%, P<0.01 for RS4;11). Western Blotting also showed that these apoptosis were mediated by p53-Caspase8 pathway. Up-reguration of S100A6 and inhibition of p53-Caspase8 pathway were also confirmed in previously established MLL/AF4 transgenic mice. These results suggest that MLL/AF4 positive ALL escapes from TNF-alpha mediated apoptosis by up-regulation of S100A6 expression followed by interfering with p53 acetylation. Our present results suggest that S100A6 may be a promising therapeutic target for MLL/AF4 positive ALL by combinating with allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

Co-Expression of Membrane-Bound Tumor Necrosis Factor-Alpha Receptor Types 1 and 2 by Tumor Cell Lines

2020 ◽  
Vol 181 (4) ◽  
pp. 249-256
Author(s):  
Alina A. Alshevskaya ◽  
Irina Belomestnova ◽  
Julia A. Lopatnikova ◽  
Julia Zhukova ◽  
Irina Evsegneeva ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Cell ◽  
Cell Lines ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Tumor Cell Lines ◽  
Necrosis Factor Alpha ◽  
Membrane Bound ◽  
Factor Alpha ◽  
Necrosis Factor

scholarly journals The effects of tumor necrosis factor-alpha on early human hematopoietic progenitor cells treated with 4-hydroperoxycyclophosphamide

Blood ◽  
1990 ◽  
Vol 76 (4) ◽  
pp. 681-689
Author(s):  
J Moreb ◽  
JR Zucali ◽  
S Rueth
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Bone Marrow Cells ◽  
Leukemic Cell ◽  
Tnf Alpha ◽  
Protective Effects ◽  
Necrosis Factor Alpha ◽  
Leukemic Cell Lines ◽  
Blast Cells ◽  
Factor Alpha

We have previously reported that 20 hours' preincubation of human bone marrow cells with interleukin-1 beta (IL-1) can protect early progenitor cells from 4-hydroperoxycyclophosphamide (4-HC) cytotoxicity. Since tumor necrosis factor-alpha (TNF alpha) shares many of the biologic properties of IL-1, we have compared the protective effects of TNF alpha with IL-1 against 4-HC. Incubation of human bone marrow mononuclear cells or an enriched progenitor population for 20 hours with either TNF alpha or IL-1 resulted in the survival of an increased number of single- and mixed-lineage colonies, including replatable blast cell colonies, while only rare colonies were seen in the control group. Antibodies to TNF alpha completely abolished the protection observed with IL-1, while antibodies to IL-1 alpha and IL-1 beta decreased but did not abolish the protection seen with TNF alpha. Combinations of low doses of TNF alpha and IL-1 showed synergy in their protective effects. Furthermore, no protection was observed by IL-1, IL- 1 bone-marrow-conditioned medium (IL-1-BMCM), or TNF alpha for HL-60, K562, KG1, KG1a, and DU.528 leukemic-cell lines or primary acute myelogenous leukemic (AML) blast cells from the lethal effects of 4-HC. In the case of HL-60 and KG1a cell lines, TNF alpha preincubation resulted in increased cytotoxicity. Furthermore, preincubation of a mixture of AML cells and normal bone-marrow cells with IL-1 + TNF alpha before 4-HC resulted in the protection of normal but not leukemic progenitors. These results suggest that TNF alpha is necessary for the protection of normal, early, human hematopoietic progenitors from 4-HC, while IL-1 is not mandatory but will synergize with TNF alpha to offer increased protection. In addition, no protection from 4-HC is observed by TNF alpha, IL-1, or IL-1-BMCM for primary leukemic blast cells or leukemic cell lines.

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