Atypical Apoptotic Cell Death Induced in L929 Targets by Exposure to Tumor Necrosis Factor

Fady, Catherine; Gardner, Agnes; Jacoby, F J; Briskin, Kenneth B.; Tu, Yiping; Schmid, Ingrid; Lichtenstein, Alan

doi:10.1089/jir.1995.15.71

Cited by 44 publications

(30 citation statements)

References 27 publications

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“…TNF and VP-16 induce apoptotic death in L929 target cells As we have previously described (Fady et al, 1995), the death of L929 cells exposed to TNF is associated with the characteristic morphology of apoptosis and endonucleolytic cleavage of target cell DNA (Figure 1). These defining apoptotic changes were initiated approximately 8 ± 12 h after treatment ( Figure 1 and Mans et al, 1990), at a time when only minimal cytotoxicity was present (26+3% for 1.2610 4 pM; 12+3% for 6610 3 pM at 12 h).…”

Section: Resultsmentioning

confidence: 56%

“…The methylene blue cytotoxicity assay was performed as previously described (Fady et al, 1995). Briefly, 10 4 cells in 100 ml were dispensed into a 96 well microtitre plate, allowed to adhere overnight and then exposed to serial dilutions of TNF or VP-16 in an additional 100 ml.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

“…As previously described (Fady et al, 1995) cells were lysed in 10 mM Tris-HCl (pH 7.5), 100 mM EDTA, 0.5% SDS and 100 mg/ml of proteinase K for 18 h at 378. DNA was then extracted twice with phenol, PCI and chloroform, precipitated in ethanol, centrifuged (30 min at 10 000 g) and resuspended in TE buffer containing 100 mg/ ml of RNase for 1 h at 378.…”

Section: Electrophoresis Of Dnamentioning

confidence: 99%

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Evidence against the hypothesis that BCL-2 inhibits apoptosis through an anti-oxidant effect

Gardner

Fady

et al. 1997

Cell Death Differ

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We contrasted possible protection against apoptosis afforded by either BCL-2 expression or anti-oxidant inhibitors in the same tumor target challenged by two distinct triggers of apoptosis. Exposure of L929 fibroblasts to tumor necrosis factor (TNF) or etoposide (VP-16) induced apoptotic death with similar kinetics. Enforced expression of BCL-2 significantly protected against apoptosis induced by VP-16 but had no effect against TNF-induced apoptosis. In contrast, the antioxidants desferrioxamine, butylated hydroxyanisol and Nacetyl cysteine all inhibited TNF-induced apoptosis in a concentration-dependent fashion. Although exposure to VP-16 resulted in a significant generation of intracellular oxyradicals, the above three anti-oxidant inhibitors had no effect on VP-16-induced apoptotic death. Interestingly, enforced expression of BCL-2 also inhibited the ability of VP-16 to generate oxy-radicals and to depress intracellular glutathione levels. These results indicate that BCL-2 can exert anti-oxidant effects but argue against the hypothesis that these effects are critical to its protection against apoptosis.

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Section: Resultsmentioning

confidence: 56%

Section: Cytotoxicity Assaymentioning

confidence: 99%

Section: Electrophoresis Of Dnamentioning

confidence: 99%

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Evidence against the hypothesis that BCL-2 inhibits apoptosis through an anti-oxidant effect

Gardner

Fady

et al. 1997

Cell Death Differ

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“…It is important to note that proof of apoptosis often requires more than one method; this is due to the fact that not all cell death can be easily classified as either necrosis or apoptosis. There are some cells that undergo apoptosis and yet will not have the characteristic shrinkage and chromatin loss and necrosis may display some of the characteristics of apoptosis (Fady et al, 1995;Meneses-Acosta et al, 2001). …”

Section: Apoptosis Versus Necrosismentioning

confidence: 99%

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

Holmes¹,

Soprano²,

Soprano³

2004

Journal Cellular Physiology

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Apoptosis is also known as programmed cell death. Apoptosis plays an essential role in maintaining normal tissue and cell physiology in multicellular organisms. Clearance of aberrant or pre-cancerous cells occurs through the induction of apoptosis. It has been reported that many tumors and tumor cell lines have dysfunctional apoptosis signaling, causing these tumors to escape immune monitoring and internal cellular control mechanisms. One potential cause of this dysfunctional apoptosis is the tumor suppressor p53, an important regulator of growth arrest and apoptosis that is mutated in over 50% of all cancers. Retinoids have great potential in the areas of cancer therapy and chemoprevention. While some tumor cells are sensitive to the growth inhibitory effects of natural retinoids such as all-trans-retinoic acid (ATRA), many ovarian tumor cells are not. 6-[3-(1-Admantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and fenretinide N-[4-hydroxyphenyl] retinamide (4-HPR) are conformationally restricted synthetic retinoids that induce growth arrest and apoptosis in both ATRA-sensitive and ATRA-resistant ovarian tumor cell lines. Recently, we have identified the molecular pathways of apoptosis induced by treatment of ovarian carcinoma cells with mutated p53 by CD437 and 4-HPR.

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“…For example, cyclophosphamide induces a form of apoptosis in lymphocytes that is resistant to the protective effects of zinc. 39,40 The findings in this study show that exposure of iron chelators to murine thymocytes lowers intracellular zinc to levels associated with thymocyte apoptosis. The findings further show that apoptosis is induced both in vitro and in vivo by exposure to deferiprone and that zinc inhibits this process.…”

Section: Discussionmentioning

confidence: 68%

Cellular zinc content is a major determinant of iron chelator–induced apoptosis of thymocytes

Maclean

Cleveland

Porter

2001

Blood

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Desferrioxamine (DFO) and the hydroxypiridinone (HPO) deferiprone (CP20) chelate iron as well as other metals. These chelators are used clinically to treat iron overload, but they induce apoptosis in thymocytes. Thymocyte apoptosis is potentiated by zinc deficiency, suggesting that these iron chelators may induce apoptosis by depleting stores of zinc. Exposure of murine thymocytes to either DFO or deferiprone resulted in significant reductions in the labile intracellular zinc pool. Moreover, increasing intracellular zinc levels, by chronic zinc dietary supplementation to mice or in vitro loading with zinc, abrogated deferiprone-induced murine thymocyte apoptosis. Bidentate hydroxypyridinones such as deferiprone interact with intracellular zinc pools in a manner distinct from that of DFO, which is a hexadentate iron chelator. Whereas deferiprone acts synergistically with the zinc chelator NNNN-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) to induce apoptosis, DFO does not. This difference is most likely due to the ability of HPOs but not DFO to "shuttle" zinc onto acceptors such as metallothioneins. By nature of its structure, DFO is larger than deferiprone and is thus less able to access some intracellular zinc pools. Additionally, metal complexes of DFO are more stable than those of HPOs and thus are less likely to donate zinc to other acceptors. The ability of deferiprone to preferentially access zinc pools was also demonstrated by inhibition of a zinc-containing enzyme phospholipase C, particularly when combined with TPEN. These findings suggest that bidentate iron chelators access intracellular zinc pools not available to DFO and that zinc chelation is a mechanism of apoptotic induction by such chelators in thymocytes. IntroductionPatients with thalassemia and other refractory anemias require regular blood transfusions, and the most common cause of death is iron overload. Currently, desferrioxamine (DFO) is the first line treatment of transfusional iron overload, but it is orally inactive due to its high molecular weight and therefore must be given as subcutaneous infusions. Therefore, the design of an orally active, nontoxic, and selective iron chelator remains an important goal. The ideal iron chelator would prevent or modify iron-mediated pathological processes without undue toxicity.The bidentate 3-hydroxypyridin-4-ones (HPOs), of which deferiprone has been the most extensively used clinically, are a series of orally active iron chelators. Deferiprone is approximately one-third of the molecular weight of DFO and neutrally charged. Therefore, deferiprone is efficiently absorbed from the gut and enters intracellular metal pools more rapidly than DFO, where it can inhibit metalloenzymes such as ribonucleotide reductase. 1 In principle these properties could explain some of the toxic effects of this drug, which include neutropenia and bone marrow aplasia in laboratory animals 2,3 and agranulocytosis in some patients. 4,5 Although induction of bone marrow hypoplasia is dose-and time-dependent in laboratory...

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Atypical Apoptotic Cell Death Induced in L929 Targets by Exposure to Tumor Necrosis Factor

Cited by 44 publications

References 27 publications

Evidence against the hypothesis that BCL-2 inhibits apoptosis through an anti-oxidant effect

Evidence against the hypothesis that BCL-2 inhibits apoptosis through an anti-oxidant effect

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

Cellular zinc content is a major determinant of iron chelator–induced apoptosis of thymocytes

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