The conversion of 2-β-D-ribofuranosylthiazole-4-carboxamide to an analogue of NAD with potent IMP dehydrogenase-inhibitory properties

Cooney, David A.; Jayaram, Hiremagalur N.; Gebeyehu, Gulilat; Betts, C. R.; Kelley, James A.; Márquez, Víctor E.; Johns, David G.

doi:10.1016/0006-2952(82)90436-1

Cited by 139 publications

(59 citation statements)

References 6 publications

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“…12 The two nucleoside antimetabolites, TR and BR are converted in cancer cells to their active dinucleotide metabolites, TAD (thiazole-4-carboxamide adenine dinucleotide) and BAD (benzamide adenine dinucleotide), which are analogues of NAD, wherein the nicotinamide moiety is replaced by their respective bases. 11,13 BAD potently inhibits NAD utilization by IMPDH, resulting in the depletion of intracellular guanylate concentrations including GTP and dGTP.…”

Section: Introductionmentioning

confidence: 99%

Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells

et al. 1999

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One of the mechanisms of action of a new oncolytic agent, benzamide riboside (BR) is by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH) which catalyzes the formation of xanthine 5'-monophosphate from inosine 5'-monophosphate and nicotinamide adenine dinucleotide, thereby restricting the biosynthesis of guanylates. In the present study BR (10 ± 20 mM) induced apoptosis in a human ovarian carcinoma N.1 cell line (a monoclonal derivative of its heterogenous parent line HOC-7). This was ascertained by DNA fragmentation, TUNEL assay, [poly(ADP)ribose polymerase]-cleavage and alteration in cell morphology. Apoptosis was accompanied by sustained c-Myc expression, concurrent down-regulation of cdc25A mRNA and protein, and by inhibition of Cdk2 activity. Both Cdk2 and cdc25A are G 1 phase specific genes and Cdk2 is the target of Cdc25A. These studies demonstrate that BR exhibits dual mechanisms of action, first by inhibiting IMPDH, and second by inducing apoptosis, which is associated with repression of components of the cell cycle that are downstream of constitutive cMyc expression.

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Section: Introductionmentioning

confidence: 99%

Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells

et al. 1999

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“…The antitumor effects of Taz and Sel are mediated, in part, by their conversion to tiazofurin-adenine dinucleotide (TAD) and selenazofurin-adenine dinucleotide (SAD), which are analogs of NAD (4,12). TAD and SAD are synthesized by nicotinamide mononucleotide ATP *adenylyl transferase; they inhibit the NAD-dependent enzyme, inosine 5'-monophosphate (IMP) dehydrogenase, which converts IMP to guanosine 5'-monophosphate (GMP).…”

Section: Introductionmentioning

confidence: 99%

“…TAD and SAD are synthesized by nicotinamide mononucleotide ATP *adenylyl transferase; they inhibit the NAD-dependent enzyme, inosine 5'-monophosphate (IMP) dehydrogenase, which converts IMP to guanosine 5'-monophosphate (GMP). As a result of this inhibition, cells become depleted of GMP and they accumulate the precursor IMP (4,12,13). GMP depletion appears to be part of their cytotoxic mechanism since the effect of these compounds can be overcome by supplying cells with guanosine nucleosides (4).…”

Section: Introductionmentioning

confidence: 99%

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Modulation of nicotinamide adenine dinucleotide and poly(adenosine diphosphoribose) metabolism by the synthetic "C" nucleoside analogs, tiazofurin and selenazofurin. A new strategy for cancer chemotherapy.

Berger¹,

Berger²,

Catino³

et al. 1985

J. Clin. Invest.

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Tiazofurin (2-8-D-ribofuranosylthiazole4-carboxamide) and selenazofurin (2-%-D-ribofuranosylselenazole4-crboxmiude) are synthetic 'C" nucleosides whose antineoplastic activity depends on their conversion to tiazofurin-adenine dinucleotide and selenazofurin-adenine dinucleotide which are analogs of NAD. The present study was conducted to determine whether these nucleoside analogs and their dinucleotide derivatives interfere with NAD metabolism and in particular with the NADdependent enzyme, poly(ADP-ribose) polymerase. Incubation of L1210 cells with 10 gM tiazofurin or selenazofurin resulted in inhibition of cell growth, reduction of cellular NAD content, and interference with NAD synthesis. Using 114Clnicotinamide to study the uptake of nicotinamide and its conversion to NAD, we showed that the analogs interfere with NAD synthesis, apparently by blocking formation of nicotinamide mononucleotide. The analogs also serve as weak inhibitors of poly(ADPribose) polymernse, which is an NAD-utilizing, chromatinbound enzyme, whose function is required for normal DNA repair processes. Continuous incubation of L1210 cells in tiazofurin or selenazofurin resulted in progressive and synergistic potentiation of the cytotoxic effects of DNA-damaging agents, such as 1,3-bis(2-chloroethyl)-1-nitrosourea or N-methyl-N'-nitro-N-nitrosoguanidine. These studies provide a basis for designing chemotherapy combinations in which tiazofurin or selenazofurin are used to modulate NAD and poly(ADP-ribose) metabolism to synergistically potentiate the effects of DNA strand-disrupting agents.

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“…The cell line was selected by continuous exposure to increasing concentrations of tiazofurin (TZ). TZ (2-,-D-ribofuranosylthiazole-4-carboxamide) is converted to an analogue of NAD (TAD) in which the thiazole-4-carboxamide moiety replaces nicotinamide (Jayaram et al, 1982). TAD is a potent inhibitor of IMP dehydrogenase (Cooney et al, 1982).…”

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confidence: 99%

Low nicotinamide mononucleotide adenylyltransferase activity in a tiazofurin-resistant cell line: effects on NAD metabolism and DNA repair

Boulton

Kyle²,

Durkacz³

1997

Br J Cancer

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Summary Poly(ADP-ribose) polymerase (PADPRP), which uses NAD to synthesize ADP-ribose polymers, is activated by DNA strand breaks and mediates cellular responses to DNA damage. The consequences of low cellular NAD levels in a cell line deficient in nicotinamide mononucleotide adenylyltransferase (NMNAT), an enzyme essential for NAD biosynthesis, were investigated by assessing NAD metabolism and DNA repair after treatment with alkylating agents. A tiazofurin-resistant L1210 cell line (TZR) was isolated. NAD levels were approximately 5933 and 3375 pmol mg-1 protein for parental (wild type, WT) and TZR cells respectively, and NMNAT levels were reduced by > 95%. TZR cells were more sensitive to temozolomide (TM) and 1 -methyl-3-nitro-1 -nitroso-guanidine (MNNG), particularly at concentrations that caused > 50% NAD depletion. TM and MNNG treatment decreased NAD levels in both cell lines, but took longer to return to control levels in TZR cells. For example, MNNG (5 gM), depleted NAD levels at 6 h to approximately 4512 (WT) and 1442 (TZR) pmol mg-1 protein; however, NAD levels had returned to control levels by 8 h in WT cells, but were not restored by 16 h in TZR cells. Both cell lines were equisensitive to the growth-inhibitory effects of NU1025 per se (IC50 370 ,UM). Co-exposure of the cell lines to TM (100 gM) with increasing concentrations of NU1025 led to a synergistic enhancement of cytotoxicity, with IC50 values for NU1025 decreasing to 17 ± 4,gM (TZR) and 37 ± 6 gM (WT). A similar enhanced sensitivity to NU1025 (approximately 2.7-fold) was obtained when TZR cells were co-exposed to MNNG + NU1025. TM-induced DNA strand breaks were increased by co-incubation with NU1025, and again the TZR cell line showed increased sensitivity to NU1025. There were no significant changes in NMNAT activity in response to MNNG treatment over 24 h, either in the presence or in the absence of NU1025. These data demonstrate that modest decreases in cellular NAD levels can sensitize cells to alkylating agents and PADPRP inhibitors.

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The conversion of 2-β-D-ribofuranosylthiazole-4-carboxamide to an analogue of NAD with potent IMP dehydrogenase-inhibitory properties

Cited by 139 publications

References 6 publications

Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells

Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells

Modulation of nicotinamide adenine dinucleotide and poly(adenosine diphosphoribose) metabolism by the synthetic "C" nucleoside analogs, tiazofurin and selenazofurin. A new strategy for cancer chemotherapy.

Low nicotinamide mononucleotide adenylyltransferase activity in a tiazofurin-resistant cell line: effects on NAD metabolism and DNA repair

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