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Department of Human Biology and Nutritional Sciences and
*
Department of Pathobiology, University of Guelph, Guelph, ON, Canada N1G 2W1;
Laboratory for Skin Cancer Research, Hospital Research Center of University Laval, Ste. Foy, QC, Canada G1V 4G2; and
**
Unit of Health and Environment, Hospital Research Center of University Laval, Ste. Foy, QC, Canada G1V 4G2
2To whom correspondence should be addressed. E-mail: jkirklan{at}uoguelph.ca.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • niacin • leukemia • nitrosourea • poly(ADP-ribose) • chemotherapy • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–3
). Ethylnitrosourea (ENU)3
is a monofunctional ethylating agent that we have used as a simple model of the more complex chemotherapeutic nitrosoureas. We have shown, in a companion paper (4
), that ENU is a potent leukemogen in Long-Evans rats. The alkylating capacity of nitrosoureas is the primary cause of their leukemogenic potential, due to the low content of alkyltransferase protein in the bone marrow (5
). During excision repair, removal of the modified base and neighboring nucleotides creates a strand break, which activates the nuclear enzyme, poly(ADP-ribose) polymerase (PARP). PARP uses NAD+ as a substrate in the synthesis of poly(ADP-ribose), creating a cloud of negatively charged poly(ADP-ribose) at the site of DNA damage. This may play several roles, including regulation of excision repair, p53 function and apoptosis (6
). The most consistent evidence, however, shows that poly(ADP-ribose) synthesis prevents recombination events at the site of damage, probably by repelling other DNA strands, thereby decreasing the risk of chromosomal translocations (6
,7
). This is critical in the bone marrow because most leukemias are caused by translocation events of this nature (8
). Previous work from our laboratory showed that niacin deficiency in rats causes a dramatic decrease in bone marrow NAD+ levels and poly(ADP-ribose) (4
). During exposure to ENU, they display more severe anemia and leukopenia (9
). The rats that were niacin deficient during ENU exposure had a decreased latency of tumor development and they developed a greater average number of malignancies per rat, compared with pair-fed controls receiving the recommended intake of niacin (4
).
Pharmacologic doses of nicotinic acid (NA) and nicotinamide (Nam) are currently being used for the treatment of hyperlipidemia and insulin-dependent diabetes, respectively (10
,11
). It is important to determine whether pharmacologic supplementation of niacin has the potential to further increase bone marrow NAD+ and poly(ADP-ribose) and decrease the short- and long-term hematologic effects of DNA damage in the bone marrow. Niacin may be supplemented in the form of NA or Nam. Although both can support NAD and NADP production, they also have additional pharmacologic effects that may differ between the two vitamin forms (12
). Both have the potential to increase the amount of NAD+ available for PARP activity, potentially increasing the repair capability or resistance to recombinational events in the bone marrow of chemotherapy patients. However, there have been reports of cancer patients experiencing toxic effects from therapeutic doses of Nam when it is used as a radiosensitizer (13
), and there are a variety of side effects associated with large doses of NA (10
). It is important to characterize the effects of pharmacologic supplementation of the two forms of niacin on bone marrow as a first step toward recommendations regarding niacin status and the chemotherapy patient. In this paper, we examined the dose response of bone marrow NAD+ to large dietary intakes of NA and Nam, and the effect of these supplements on ENU-induced poly(ADP-ribose) accumulation, acute bone marrow suppression and long-term development of cancers. Unlike the companion niacin-deficiency study(4
), which used a basal diet that was limited in tryptophan and complicated by feed restriction, this study examines the response to additional niacin in a high quality diet containing 20% protein, adequate niacin and only a small degree of feed restriction.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Ethylnitrosourea, Modified Wright Giemsa Stain and reagents for NAD analysis were purchased from Sigma Chemical (St. Louis, MO). Halothane, B.P. anesthetic was obtained from MTC Pharmaceuticals (Cambridge, Canada). Isotone II and Zap-oglobin II were purchased from Coulter Electronics of Canada, (Burlington, Canada). Buffered formalin (100 g/L) was purchased from Fisher Scientific (Ottawa, Canada). Reagents for gel electrophoresis were obtained from BioRad Laboratories (Mississauga, Canada).
Animals.
As described in the companion paper (4
) we designed a model of alkylation-based chemotherapy based on ENU treatment of Long-Evans rats. Rats were housed and treated in accordance with the guidelines of the Canadian Council on Animal Care. Male Long-Evans rats were obtained at weaning (40–50 g; 3 wk old; Charles River Canada, St. Constant, Canada), housed in suspended wire- bottomed cages and given free access to water with a 12-h light:dark cycle. Feed intake was determined daily.
Diets.
A preliminary dose response was conducted to determine the levels of NA and Nam to use in the diets (Fig. 1
). Male Long-Evans rats (3 wk old) were fed a 20% casein-based diet (AIN-93M) (14
) supplemented with either 0.03 g nicotinamide (Nam)/kg diet (PF, i.e., pair-fed control), or 2, 4 or 6 g of nicotinamide/kg or nicotinic acid (NA)/kg diet. The PF and NA rats were pair-fed to the intake of the Nam rats, which had a slightly lower food intake. These results led to the continued use of 4 g/kg diet for both NA and Nam.
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Using ENU, we simulated a chemotherapy protocol in nontumor-bearing rats. Rats were gavaged with 12 doses of either 30 mg ENU/kg body in water (pH 4.0), or an equivalent volume of water (pH 4.0) alone (CON) (from 4 to 7 wk of age). At this point, all rats were fed the AIN-93M diet (14
) and monitored for the development of tumors or for weight loss. This model approximates the treatment of a cancer patient, with various levels of pharmacologic niacin supplementation, followed by a recovery period with a return to a standard diet. During the second phase of the experiment (AIN-93M), the rats were fed an equal amount of diet per unit body weight each day to ensure similar energy intakes throughout the remainder of the trial. Blood samples were taken at the start of the experiment and every 8 d until 2 wk after ENU treatment ended. Hematocrit, and circulating lymphocytes and neutrophils were quantified, as described earlier (9
), to determine the effect of niacin supplementation on the acute effects of ENU treatment.
Cancer development.
Rats that developed palpable tumors > 1 cm in diameter or lost >5% of their maximal body weight were killed; necropsies were performed to determine the nature of the cancer(s) involved. The rats were gaining weight normally throughout the experiment, and a 5% loss in body weight was almost invariably associated with a relatively advanced neoplasm of some type. Tissue sections were fixed in buffered formalin (100 g/L) and then embedded in paraffin, sectioned, affixed to slides and then stained with hematoxylin and eosin. Control rats were killed at 52 wk of age and autopsies were performed.
Acute response to ENU; NAD+ and poly(ADP-ribose) analysis.
We previously conducted a time course after ENU treatment and found an early peak in poly(ADP-ribose) levels at 3 h; this time point was used therefore to determine the interaction of niacin supplementation and ENU treatment. After 3 wk of consumption of pair-fed or supplemented diets, rats were treated with a single dose of ENU or vehicle, as described earlier in this paper, except that the dose used was 100 mg/kg body rather than 30 (to create larger amounts of poly(ADP-ribose) for ease of quantification). Bone marrow was processed as described in the companion paper (4
).
For analysis of NAD+, the cell suspension from one femur was acidified with concentrated perchloric acid and analyzed as described in the companion paper (4
). For analysis of poly(ADP-ribose), cells from the second femur were centrifuged, extracted and immunoblotted with antibody 96–10, as described in the companion paper (4
). This type of gel shows total poly(ADP-ribose) content, the size of proteins that are acting as acceptors and gives some idea of poly(ADP-ribose) chain, from the length of the smears (15
).
Analysis of data.
Morbidity curves were analyzed by probit and 
2 analyses. Differences in growth and NAD+ were analyzed by two-way ANOVA using the General Linear Modeling procedure (SAS/PC, SAS Institute, Cary, NC). In the case of significant differences in the ANOVA model, means were compared by Duncan’s New Multiple Range test. Differences in cancer types in Table 1
were tested by the two-sided Fisher’s Exact test; average leukemias/rat were tested by t test, due to the presence of more than one leukemia in some rats. In all cases, differences with P < 0.05 were considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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. An opposite, and more expected pattern was observed with Nam supplementation, with significant elevations at 4 and 6 g/kg diet. On the basis of these results and concerns over feed refusal in the 6 g/kg Nam group, 4 g/kg diet NA and NAM were chosen for the ENU-treatment trial.
Rats supplemented with Nam at 4 g/kg diet displayed a small degree of feed refusal, making it necessary to pair-feed the PF and NA rats to the Nam group. Growth did not differ among diet groups until wk 10 when all three diet groups displayed a delayed and transient ENU-induced growth depression (Fig. 2
). There were no further body weight differences, showing the effectiveness of controlled food intake.
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). In the current study, ENU caused the expected neutropenia (data not shown) and lymphopenia (Fig. 3
), but neither NA nor Nam supplementation significantly affected the response of blood cell variables to ENU. There were trends for Nam to decrease hematocrit and neutrophil and lymphocyte numbers, and this was most notable in the lymphocyte data (Fig. 3)
.
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2 = 6.82, P = 0.145) (Fig. 4A
). This may have been resolved with an increase in the number of replicates, but it was not feasible to conduct the experiment again. Because both forms of the vitamin elevated bone marrow NAD+ and poly(ADP-ribose) levels to the same degree (see subsequent figures), the data from the NA and Nam curves were combined (Fig. 4
B). Analysis of the pooled data showed a significant delaying effect of supplementation on cancer incidence [latency to 50% morbidity (LT50) for PF = 23.5, LT50 for combined = 25.5, 2 = 10.22). In contrast to the effects of niacin deficiency, which were most pronounced in the early to middle phases of the survival curve (4
), this effect was greater later in the progression, with a delay of 8 wk in the LT90 (latency to 90% morbidity). It is important to note that the controls were well nourished and were receiving an adequate intake of niacin (30 mg/kg diet). No water-gavaged rats became moribund due to neoplastic disease.
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shows the necropsy results from ENU-treated rats. Leukemias were the predominant cause of morbidity. Malignant and total stromal tumors were more frequent in the combined supplementation group than in the PF group (2-tailed Fisher’s Exact test). The average number of leukemias per rat did not differ between groups (0.75 ± 0.14 in PF rats and 0.55 ± 0.10 in the combined niacin supplemented groups).
Niacin supplementation dramatically affected blood and bone marrow NAD+ concentrations (Fig. 5
). Supplementation with either NA or Nam doubled blood NAD+ (Fig. 5
A). Blood NAD+ was not altered 3 h after ENU treatment, which was expected due to the lack of DNA and PARP in RBC, which carry the majority of blood NAD+. Bone marrow NAD+ increased 1- and 1.5-fold in response to supplementation with NA or Nam, respectively (Fig. 5
B). There was a significant ENU-induced depression of NAD+ in the Nam-supplemented group. This may reflect the extensive poly(ADP-ribose) synthesis taking place in the supplemented bone marrow cells (see below), but it was not observed in the NA-ENU group.
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shows immunoblot analysis of protein-bound poly(ADP-ribose), using a polyclonal antibody raised to a poly(ADP-ribose)-bovine serum albumin conjugate (15
). Standards of control and diethylnitrosamine (DEN)-treated liver were created in vivo as previously described (16
) and quantified by HPLC analysis. The control and DEN-treated lanes contained 45 and 227 fmol of poly(ADP-ribose)/lane, respectively, and were used as internal standards to quantify the bone marrow samples. The blots provide information on the total quantity of poly(ADP-ribose) (total density of lane), the molecular weight of major acceptor proteins (lower edge of distinct bands) and, to some extent, the length or number of poly(ADP-ribose) chains on a given acceptor (the length of the smear above a clear acceptor protein) (15
). For example, the large smear of reactivity originating at 116 kDa in the DEN-treated liver sample represents the automodification of poly(ADP-ribose) polymerase with multiple, long-chain polymers (17
). The blots in Figure 6
used composite samples from four different rats for each lane to provide a representative result. Those samples were run individually on separate blots; after background subtraction and thresholding, the total gray in each lane was determined. The bone marrow lanes were loaded by nucleated cell number and they appeared identical (loading density and pattern of bands) by fast green staining before immunoblotting. Densitometry analysis was used to prepare the graphs in the lower panel of Figure 6
. Supplementation with Nam and NA caused 5- and 3.4-fold increases in basal poly(ADP-ribose) levels (Nam-CON, NA-CON), respectively. ENU treatment alone (PF-ENU) induced a 4.5-fold increase in poly(ADP-ribose) in PF rats, and supplementation with either NA or Nam increased this response to ENU by 1.5-fold (Nam-ENU, NA-ENU).
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116 and 90 kDa, and likely represented automodification of PARP and its proteolytic fragment (associated with apoptosis) (18
). ENU treatment caused widespread formation of poly(ADP-ribose), with strong labeling in the 90- and 116-kDa regions, and diffuse labeling through to very-low-molecular-weight acceptors. There was a distinct band between 116 and 205 kDa, which was often obscured by the 116-kDa smear. Supplementation with Nam or NA caused a selective increase in the 116-kDa smear, and in combination with ENU, both supplements induced strong labeling of the 90-kDa smear and diffuse modification through a wide range of molecular weights. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) and the long-term development of cancers (4
). In this study we showed that niacin supplementation above the traditional requirement carries further benefits to long-term survival. We also showed that niacin supplementation dramatically increased NAD+ and poly(ADP-ribose) levels in bone marrow compared with diets containing the required amount of niacin. The data in this and previous papers (4
,9
) support an association of susceptibility and protection with bone marrow NAD+ and poly(ADP-ribose) levels. In comparing the deficiency (4
) and supplementation models (Fig. 5)
, the full range of bone marrow NAD+ concentration varies >30-fold, from 8 to 250 pmol/106 cells. More dramatically, ENU-induced poly(ADP-ribose) accumulation varies 65-fold, from 10 to 650 fmol/106 cells in the deficient (4
) and supplemented (Fig. 6)
marrows, respectively. These results are the most dramatic demonstration of the responsiveness of NAD and poly(ADP-ribose) metabolism to dietary changes in a whole-animal model.
Pharmacologic supplementation of NA (2 to 6 g/d) is used widely in the treatment of hyperlipidemia in humans, causing decreased blood triglycerides and LDL cholesterol and an increase in HDL cholesterol (19
,20
). NA may act on blood lipids through the inhibition of adenylate cyclase (21
) or ß-hydroxyl-ß-methyl glutarate-CoA reductase (19
). Extended use of large supplements of nicotinic acid is associated with a decrease in all-cause mortality (22
), which may be suggestive of benefits beyond regulation of blood lipids. Pharmacologic supplementation of nicotinamide (3 g/d) is currently being tested in several large clinical trials for efficacy in the prevention of insulin-dependent diabetes mellitus in high risk children (23
). Although the most commonly proposed mechanism involves the inhibition of PARP and protection of NAD pools, data in this paper do not support this (see below). Consumption of 3–6 g of NA or Nam by humans is similar to the 4 g/kg diet used in these experiments, when compared on the basis of dry matter or energy intake.
Although neither NA nor Nam alone displays carcinogenic activity (24
), administration of pharmacologic doses of Nam to laboratory rats and mice during or after carcinogen or radiation exposure has had mixed effects on genotoxicity (24
–26
). Nam is an inhibitor of PARP, although the 50% inhibitory concentration is rather high, varying in different studies from 31 to 210 µmol/L (27
,28
). Many researchers have proposed that Nam acts as a PARP inhibitor when used in whole animals. However, it is difficult for tissue Nam levels to reach a high concentration because excess dietary Nam is methylated in the liver and excreted, and Nam that reaches tissues is metabolized to NAD+. Nam may prevent cell death during severe genotoxicity by maintaining NAD levels rather than through the inhibition of PARP. In addition, other researchers have shown that Nam acts as a radiosensitizer by increasing blood flow and decreasing hypoxia (26
). It is possible that chemosensitization also results from increased blood flow and drug delivery to certain tissues. When utilized as a radiosensitizer, Nam is usually delivered intravenously and will initially by-pass the liver, allowing high levels to reach tissues. The role of Nam as an oral, in vivo PARP inhibitor is poorly supported. In this study, we noted significant increases in bone marrow NAD+ after dietary supplementation of NA and Nam (Fig. 4
D) as well as identical increases in poly(ADP-ribose) levels after ENU (Figs. 5
B, 6). These results prove that Nam is not functioning in our model as a PARP inhibitor, and the similar effects of NA and Nam in this study implicate the increase in bone marrow NAD+ and poly(ADP-ribose) in protection against the effects of ENU.
It is important to notice the overall difference in protein and energy intake between the deficiency (1
,2
) and supplementation models. The basal supplementation diet contained higher quality protein and the degree of feed restriction was much less severe than in the deficiency model; thus, growth rates were greater in the supplementation trial (Fig. 2)
compared with the deficiency trial (2
). In the long term, this caused a more potent initiation of leukemias in the supplementation study and prevents a direct comparison of results, even between the PF controls, from the deficiency and supplementation models. Both models produced neoplasms more rapidly than expected (all of the rats treated with ENU developed cancer and were euthanized by 10 mo of age), and it is possible that the effects of niacin deficiency and supplementation might have been more pronounced if the model had been less severe.
In conclusion, the data presented here show that pharmacologic supplementation with NA or Nam caused very similar and dramatic effects on bone marrow NAD+ and poly(ADP-ribose) metabolism. Combined analysis of the supplemented groups showed lengthened latency of ENU-induced cancer development relative to well-nourished controls. Across the spectrum of niacin deficiency (4
) through pharmacologic supplementation, the changes in cancer latency correlate with changes in NAD+ and poly(ADP-ribose) levels and suggest that niacin supplementation may help to protect certain tissues from the long-term effects of DNA damage.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: CON, vehicle-gavaged control; DEN, diethylnitrosamine; ENU, ethylnitrosourea; LT50, latency time to 50% morbidity; LT90, latency time to 90% morbidity; NA, nicotinic acid; Nam, nicotinamide; PARP, poly(ADP-ribose) polymerase; PF, pair-fed.
Manuscript received 29 March 2001. Initial review completed 3 May 2001. Revision accepted 1 October 2001.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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