Role of nicotinamide adenine dinucleotide and adenosine triphosphate in glucocorticoid-induced cytotoxicity in susceptible lymphoid cells.

Berger, Nathan A.; Berger, Sosamma J.; Sudar, Donna C.; Distelhorst, Clark W.

doi:10.1172/jci112989

Cited by 32 publications

(5 citation statements)

References 26 publications

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“…Our findings indicated that these two processes acted in an additive fashion to promote cellular DNA loss and, hence, suggest that independent mechanisms mediate this process. Previous reports propose that glucocorticoid-induced lymphocyte cell death is mediated by the activation of ADP ribosylation (via glucocorticoid-induced nicks in DNA) and subsequent cellular depletion of nicotinamide adenine dinucleotide and ATP reserves (23). Based on this rationale, it would be predicted that inhibitors of ADP ribosylation protect against loss of cell viability and decrease acridine orange binding in the presence of glucocorticoids.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Glucocorticoid Actions on Rat Thymocyte Deoxyribonucleic Acid by Fluorescence-Activated Flow Cytometry*

1988

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Glucocorticoids induce thymocyte cell death via mechanisms that occur in concert with internucleosomal DNA cleavage. To further study this process at the single cell level, glucocorticoid effects on rat thymocyte DNA were analyzed using fluorescence-activated flow cytometry. Thymocytes were isolated from adrenalectomized rats, treated in vitro with steroid hormones, stained with 0.1 mM acridine orange, and analyzed by flow cytometry. After 5 h of treatment with 10(-7) M dexamethasone a population of thymocytes with reduced acridine orange binding was observed. Thymocyte viability after glucocorticoid treatment was greater than 95%, indicating that the observed changes in dye binding occurred before cell death. Induction of this subpopulation of thymocytes was both time and steroid concentration dependent, being detectable within 2 h of in vitro steroid treatment. This response to glucocorticoids was blocked by the glucocorticoid receptor antagonist RU 486, indicating a steroid receptor-mediated process. Furthermore, both actinomycin D and cycloheximide blocked the appearance of this glucocorticoid effect, thus demonstrating a dependence upon RNA and protein biosynthesis, respectively. Incubation of thymocytes with inhibitors of DNA repair (aminobenzamide or methylnicotinamide) also diminished acridine orange binding to thymocytes. The effects of these DNA repair inhibitors and glucocorticoids were additive, suggesting independent mechanisms of action. Dexamethasone treatment (10(-7) M) of cells that fail to die in response to glucocorticoids (HeLa S3) had no effect on dye binding. These findings are consistent with the concept that glucocorticoids induce a lysis gene product that alters the thymocyte genome and thus leads to cell death.

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Section: Discussionmentioning

confidence: 99%

Analysis of Glucocorticoid Actions on Rat Thymocyte Deoxyribonucleic Acid by Fluorescence-Activated Flow Cytometry*

1988

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“…Analysis of the falls in NAD and ATP associated with 100 nM dexamethasone-stimulated apoptosis showed that a 50% fall in NAD was accompanied by only a modest change in cellular ATP; this is consistent with the maintenance of ATP during apoptotic cell death. However, Burger et al [41] showed, in the same cell line, that the fall in NAD and ATP was parallel when 1/zm dexamethasone was used.…”

Section: Endonuclease Activationmentioning

confidence: 98%

Apoptosis induced by anticancer drugs

1992

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Most of the cytotoxic anticancer drugs in current use have been shown to induce apoptosis in susceptible cells. The fact that disparate agents, which interact with different targets, induce cell death with some common features (endonucleolytic cleavage of DNA, changes in chromatin condensation) suggests that cytotoxicity is determined by the ability of the cell to engage this so-called 'programmed' cell death. The mechanism of the coupling of a stimulus (drug-target interaction) to a response (cell death) is not known, but modulation of this coupling may affect the outcome of drug treatment. This review surveys the recent evidence which supports the idea that the drug-target interaction per se is not the sole determinant of cellular sensitivity of cytotoxic drugs. Studies of the signals which might engage apoptosis, the genes which modulate it and the biochemical process of drug-induced apoptosis itself are described, where possible, for glucocorticoids, topoisomerase inhibitors, alkylating agents, antimetabolites and antihormones. It is suggested that identification of the gene products which couple the stimulus to the response, and so determine intrinsic cellular sensitivity (and resistance), will be important targets for new types of drugs. These might then allow responses to occur in the major cancers of man, which are chemoresistant.

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“…Our results show a significant increase of apoptotic cells over the 7-day period of culture compared to freshly isolated thymocytes. In addition, a reason for massive thymocytes death in ATOC might be depletion of energy reserves (Berger et al, 1987). Interestingly, after 24 hours in ATOC about half of all thymocytes were either dead or dying by apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Rat thymocytes differentiation in adult thymus organ culture

Rakin¹,

Kuštrimović²,

Kosec³

et al. 2011

Acta vet. (Beogr.)

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To investigate the differences between thymocytes development in vivo and in vitro, thymus lobe fragments from 12-weeks old male Albino Oxford rats were cultivated over a 7-days period. In the controls and cultivated thymic lobes fragments were evaluated and the viability, apoptosis and cell cycle of thymocytes, as well as the histological characteristics of thymic tissue. Additionally, we analyzed the expression of CD4, CD8 and TCRαβ on thymocytes by flow cytometry. The obtained results showed that thymus cellularity decreased during cultivated time due to expanded apoptosis, decreased proliferation and the absence of progenitors reseeding thymus. The relative proportion of thymocyte subsets in the first 24 hours of culture remained similar as in the control. However, cultivation for 3 and 7 days modulated the relative proportions between thymoctye subsets. The percentage of DP TCRαβlow increased, DP TCRαβhi subset remained unchanged, both SP TCRαβhi subsets decreased while the same mature SP phenotype dominated in culture media. These results demonstrate that cultivated thymic fragments retain the capacity for T cell development, although cultivation modulates this process

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Role of nicotinamide adenine dinucleotide and adenosine triphosphate in glucocorticoid-induced cytotoxicity in susceptible lymphoid cells.

Cited by 32 publications

References 26 publications

Analysis of Glucocorticoid Actions on Rat Thymocyte Deoxyribonucleic Acid by Fluorescence-Activated Flow Cytometry*

Analysis of Glucocorticoid Actions on Rat Thymocyte Deoxyribonucleic Acid by Fluorescence-Activated Flow Cytometry*

Apoptosis induced by anticancer drugs

Rat thymocytes differentiation in adult thymus organ culture

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