Inhibition of poly(ADP‐ribose) polymerase by methylated xanthines and cytokinins

Levi, Viktorya; Jacobson, Elaine L.; Jacobson, Myron K.

doi:10.1016/0014-5793(78)80627-9

Cited by 64 publications

(12 citation statements)

References 25 publications

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“…Similar results were also observed in other rodent cell lines [25]. Caffeine may enhance X-rayinduced HeLa cell killing [26] or L-cell killing by alkylating agents [27] in a similar way, because caffeine also has been shown to inhibit poly(ADPribose) synthetase [28]. The enhancement by poly-(ADP-ribose) synthetase inhibitors of cell killing effect of DNA damaging agents may have therapeutic potential in the treatment of human cancer.…”

Section: Discussionsupporting

confidence: 74%

Poly(ADP‐ribose) synthetase inhibitors enhance streptozotocin‐induced killing of insulinoma cells by inhibiting the repair of DNA strand breaks

Yamamoto

Okamoto

1982

FEBS Letters

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Section: Discussionsupporting

confidence: 74%

Poly(ADP‐ribose) synthetase inhibitors enhance streptozotocin‐induced killing of insulinoma cells by inhibiting the repair of DNA strand breaks

Yamamoto

Okamoto

1982

FEBS Letters

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“…Other studies have also generally observed normal or near normal levels of UDS in cells heterozygous for the XP genotype [15, 161. To examine further for a possible relationship between poly(ADP-ribose) synthesis and UDS, we have measured UDS following UV or MNNG treatment in normal cells in the presence of theophylline (Table 11). Theophylline is a potent inhibitor of poly(ADP-ribose) polymerase [20] and addition of 2 mM theophylline to the culture medium blocks over 90% of the conversion of NAD to poly(ADPribose) [17]. The data show that the presence of theophylline has no appreciable effect on the UDS induced by either UV or MNNG under these conditions.…”

Section: Resultsmentioning

confidence: 83%

Unscheduled synthesis of DNA and poly(ADP‐ribose) in human fibroblasts following DNA damage

McCurry

Jacobson

1981

J. Supramol. Struct. Cell. Biochem.

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Unscheduled DNA synthesis has been measured in human fibroblasts under conditions of reduced rates of conversion of NAD to poly)ADP-ribose). Cells heterozygous for the xeroderma pigmentosum genotype showed normal rates of UV induced unscheduled DNA synthesis under conditions in which the rate of poly(ADP-ribose) synthesis was one-half the rate of normal cells. The addition of theophylline, a potent inhibitor of poly(ADP-ribose) polymerase, to the culture medium of normal cells blocked over 90% of the conversion of NAD to poly(ADP-ribose) following treatment with UV or N-methyl-N'-nitro-N-nitro-soguanidine but did not affect the rate of unscheduled DNA synthesis.

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“…Both these enzyme are inhibited by nicotinamide derivatives, in particular by 5-methylnicotinamide [26,29], but not by nicotinic acid. In addition, the polymerase is inhibited by the methylxanthines [18,19,27,28] and by thymidine [29]. Of the methylxanthines, theophylline and theobromine are an order of magnitude better than caffeine [30] (and H. Halldorsson, unpublished work).…”

Section: Discussionmentioning

confidence: 99%

The Involvement of Poly(ADP‐ribose) Polymerase in the Degradation of NAD Caused by γ‐Radiation and N‐Methyl‐N‐Nitrosourea

Skidmore

Davies

Goodwin

et al. 1979

European Journal of Biochemistry

262

103

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Both N-methyl-N-nitrosourea and y-radiation lower cellular NAD in mouse leukaemia cells (L1210) in a dose-dependent way. The minimum NAD level is reached 2 h after a brief exposure to N-methyl-N-nitrosourea, but within 15 min of y-irradiation. The cells remain metabolically active ; they are able to recover their control NAD levels and are impermeable to trypan blue.Several inhibitors of poly(ADP-ribose) polymerase inhibit the drop in cellular NAD caused by these two agents: 2 mM 5-methylnicotinamide, 1 mM theophylline or 1 mM theobromine inhibit the effect of N-methyl-N-nitrosourea on cellular NAD level; 200 pM thymidine, 500 pM 5-methylnicotinamide, 500 pM theophylline and 500 pM theobromine prevent the lowering of cellular NAD by y-irradiation. The extent to which the drop in cellular NAD is inhibited is dependent on both the concentration of cytotoxic agent and of polymerase inhibitor. Caffeine will inhibit the drop in NAD but only at 10 mM, while nicotonic acid is ineffective even at this dose.The activity of poly(ADP-ribose) polymerase in permeabilized cells immediately after y-radiation increases with dose up to 12 krad, giving a maximal 3.4-fold stimulation of the enzyme activity, whereas the degradation of NAD under conditions optimal for NAD glycohydrolase does not change. The activity of the polymerase shows a close temporal correlation with the NAD drop following both y-radiation and N-methyl-N-nitrosourea. The enzyme activity is maximal when the NAD content is decreasing at the highest rate and has returned to normal levels when it ceases falling.In permeabilized cells we can distinguish poly(ADP-ribose) polymerase and NAD glycohydrolase activity by their differential response to inhibitors. The polymerase is sensitive to 5-methylnicotinamide, theophylline, theobromine and thymidine ; the NAD glycohydrolase is sensitive to 5-methylnicotinamide and theophylline, but not to theobromine and thymidine.We propose that the decrease in cellular NAD level produced by y-radiation and by N-methyl-Nnitrosourea is caused by an increased flux through poly(ADP-ribose) mediated by an increased activity of poly(ADP-ribose) polymerase. This consequently lowers the cellular NAD level. This hypothesis implies an involvement of (ADP-ribose), in the cellular response to cytotoxic drugs.In 1956, Roitt was the first to show that cytotoxic agents inhibit glycolysis due to a lowering of the cellular NAD level [l]. He used the ethyleneimines, a group of alkylating agents, but other workers have observed a marked decrease in cellular NAD following ionizing radiation [2 -41.Abbreviations. ADP-ribose, adenosine(S')diphospho(S)-P-D-ribose; (ADP-ribose),, mixture of ADP-ribose, oligo(ADP-ribose) and poly(ADP-ribose); EGTA, ethylenebis(oxoethylenenitri1o)tetraacetic acid ; Hepes, 4-(2-hydroxyethyl)-l-piperazineethanesulphonic acid; Mes, 4-morpholineethanesulphonic acid ; S.D., standard deviation of the mean.Enzymes. NAD glycohydrolase (EC 3.2.2.6); poly(ADP-ribose) polymerase (EC 2.7.7.-).Streptozotocin, the methylnitrosourea deri...

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Inhibition of poly(ADP‐ribose) polymerase by methylated xanthines and cytokinins

Cited by 64 publications

References 25 publications

Poly(ADP‐ribose) synthetase inhibitors enhance streptozotocin‐induced killing of insulinoma cells by inhibiting the repair of DNA strand breaks

Poly(ADP‐ribose) synthetase inhibitors enhance streptozotocin‐induced killing of insulinoma cells by inhibiting the repair of DNA strand breaks

Unscheduled synthesis of DNA and poly(ADP‐ribose) in human fibroblasts following DNA damage

The Involvement of Poly(ADP‐ribose) Polymerase in the Degradation of NAD Caused by γ‐Radiation and N‐Methyl‐N‐Nitrosourea

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