Novel inhibitors of poly(ADP-ribose) synthetase

Purnell, Michael R.; Whish, William J. D.

doi:10.1042/bj1850775

Cited by 484 publications

(202 citation statements)

References 14 publications

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“…This could be explained by the fact that NAM is a weak PARP inhibitor, whereas NA has no effect on PARP activity. 88 A protective effect of NAM against apoptosis was also demonstrated in the in vivo studies of Klaidman et al 89 and Mukherjee et al, 90 who showed that NAM treatment prevented neuronal apoptosis produced by tertiary-butylhydroperoxide, 89 an organic peroxide, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 90 a neurotoxin. A major finding of the present study was that both NA and NAM decreased NF-kB, as measured by a decrease in the activated form of NF-kB and a decrease in protein expression of the NF-kB(p50) and NF-kB(p65) proteins.…”

Section: Discussionmentioning

confidence: 77%

“…An increase in ability to repair DNA is suggested by the role of NAD + as a substrate for PARP, a DNA repair enzyme, and the induction of GAPDH, which also functions in DNA repair through its uracil glycosylase activity. We have previously reported 27 that PARP is protective against apoptosis, since 3-aminobenzamide, a strong PARP inhibitor, 88 sensitized cells to NaDOC-induced apoptosis. In the present study, we found that both NAD + precursors were effective at preventing apoptosis, with NA consistently showing a greater protective effect.…”

Section: Discussionmentioning

confidence: 99%

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The NAD+ precursors, nicotinic acid and nicotinamide protect cells against apoptosis induced by a multiple stress inducer, deoxycholate

et al. 2000

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The bile salt, sodium deoxycholate (NaDOC), is a natural detergent that promotes digestion of fats. At high physiologic levels, NaDOC activates many stress-response pathways and induces apoptosis in various cell types. NaDOC induces DNA damage and activates poly(ADP-ribose) polymerase (PARP), an enzyme that utilizes NAD + as a substrate to repair DNA. NaDOC also induces oxidative stress, endoplasmic reticulum (ER) stress and contributes to protein malfolding. The NAD + precursors, nicotinic acid (NA) and nicotinamide (NAM) were found to protect cells against NaDOC-induced apoptosis. NA and NAM also decreased constitutive levels of both activated NF-kB and GRP78, two proteins that respond to oxidative stress. However, the mechanism by which NA and NAM protects cells against apoptosis does not involve a reduction in constitutive levels of oxidative stress. NA or NAM treatment increased the protein levels of glyceraldehyde-3-phosphate dehydrogense (GAPDH), a multi-functional enzyme, in the nucleus and cytoplasm, respectively. NAM did not activate the promoter/response elements of 13 stress response genes nor reduce intracellular non-protein thiols, suggesting that it is non-toxic to cells. NAM thus has promise as a dietary supplement to help prevent disorders involving excessive apoptosis. Cell Death and Differentiation (2000) 7, 314 ± 326.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

The NAD+ precursors, nicotinic acid and nicotinamide protect cells against apoptosis induced by a multiple stress inducer, deoxycholate

et al. 2000

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“…As shown in Figure 6( reduction in WBC counts were similarly affected by changes in nicotinamide dose as reported for the other endpoints shown in Figure 6. Since 3-aminobenzamide is a more efficient inhibitor of ADPRT than nicotinamide (Purnell & Whish, 1980), we repeated these experiments with this compound. The results are shown in Figure 7.…”

Section: Resultsmentioning

confidence: 99%

Changes in the response of the RIF-1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP-ribosyl transferase

Horsman¹,

Brown²,

Hirst³

et al. 1986

Br J Cancer

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Summary The effect of inhibitors of nuclear ADP-ribosyl transferase (ADPRT) on the cytotoxicity of melphalan (L-PAM) in the RIF-l tumour in vivo was investigated. A large single dose of nicotinamide (1000mgkg-') enhanced the tumour cell killing by L-PAM as measured by tumour cell survival. This enhancement was maximum when nicotinamide was administered within 1 h before injecting the L-PAM. When given at this time, the nicotinamide had a dose-modifying effect on all L-PAM doses tested, giving rise to a mean enhancement ratio (ER) of 2.2. Nicotinamide did not appear to inhibit the recovery from L-PAM induced potentially lethal damage. L-PAM (6mgkg-1) produced a transient drop in mouse body temperature. This effect was both increased and prolonged by nicotinamide. In addition the inhibitor also delayed the clearance of L-PAM from the plasma of C3H mice, such that the half-life of the chemotherapeutic agent was extended from 41 min to 143 min. The effect of combining L-PAM with nicotinamide doses below 1000mgkg-' was also investigated. The results showed that as the nicotinamide dose was decreased, the enhancement of the effects on body temperature, pharmacokinetics and white blood cell counts were reduced. However, a concomitant loss in the enhancement of tumour cell killing was also observed. Similar results were obtained using 3-aminobenzamide, a more efficient inhibitor of ADPRT.

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“…A range of PADPRP inhibitors, of which 3-aminobenzamide (3AB) has been the most widely used, was first developed by Purnell and Whish (1980). The demonstration that they could modulate cellular DNA repair and survival responses (Durkacz et al, 1980) al., 1992).…”

mentioning

confidence: 99%

Potentiation of temozolomide-induced cytotoxicity: a comparative study of the biological effects of poly(ADP-ribose) polymerase inhibitors

Boulton¹,

Pemberton²,

Porteous³

et al. 1995

Br J Cancer

121

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Summary Four poly(ADP-ribose) polymerase (PADPRP) inhibitors [3-aminobenzamide, benzamide, 3,4-dihydro-5-methoxyisoquinolin-1(2H)-one (PD 128763) and 8-hydroxy-2-methylquinazolin-4(3H)-one (NU1025)] were compared with respect to their effects on a number of biological end points. The following parameters were assessed: their ability to inhibit the enzyme in permeabilised L1210 cells; their ability to potentiate the cytotoxicity of temozolomide (including the cytotoxicity of the compounds per se); their ability to increase net levels of temozolomide-induced DNA strand breaks and inhibit temozolomide-induced NAD depletion. PD 128763 and NU1025 were equipotent as PADPRP inhibitors, and 40-and 50-fold more potent than benzamide and 3-aminobenzamide respectively. All the compounds acted in a concentration-dependent manner to potentiate the cytotoxicity and increase DNA strand break levels in cells treated with temozolomide. There was an excellent correlation between the potency of the compounds as PADPRP inhibitors and their effects on cell survival and DNA repair. Temozolomide treatment caused a decrease in cellular NAD levels, and this was abolished by the PADPRP inhibitors. In conclusion, the new generation of PADPRP inhibitors are at least 50-fold more effective than 3-aminobenzamide as chemopotentiators, and can be used at micromolar rather than millimolar concentrations in intact cells.

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Novel inhibitors of poly(ADP-ribose) synthetase

Cited by 484 publications

References 14 publications

The NAD+ precursors, nicotinic acid and nicotinamide protect cells against apoptosis induced by a multiple stress inducer, deoxycholate

The NAD+ precursors, nicotinic acid and nicotinamide protect cells against apoptosis induced by a multiple stress inducer, deoxycholate

Changes in the response of the RIF-1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP-ribosyl transferase

Potentiation of temozolomide-induced cytotoxicity: a comparative study of the biological effects of poly(ADP-ribose) polymerase inhibitors

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