British Journal of Cancer (2003) 88, 1480 – 1483 All rights reserved 0007 – 0920/03 $25.00 Age-related difference in susceptibility of ApcMin/+ mice towardsthe chemopreventive efficacy of dietary aspirin and curcumin S Perkins1, AR Clarke2, W Steward1 and A Gescher*,1 Cancer Biomarkers and Prevention Group, Department of Oncology, University of Leicester, Leicester Royal Inf irmary, Leicester LE2 7LX, UK; Cardiff School of Biosciences, University of Cardiff, UK The nonsteroidal anti-inflammatory drug aspirin and the spice curcumin retard adenoma formation when administered long-term to ApcMin/+ mice, a model of human familial adenomatous polyposis coli. Both agents interfere with cyclooxygenase activity. When aspirin is administered to ApcMin/+ mice only postweaning, but not before, it is inefficacious, while curcumin given postweaning is active. Here the hypothesis was tested that dietary aspirin (0.05%) or curcumin (0.2%) prevent or delay adenoma formation in offsprings when administered to ApcMin/+ mothers and up to the end of weaning, but not afterwards. Whereas curcumin was without effect when administered in this way, aspirin reduced numbers of intestinal adenomas by 21%. When aspirin given up to the end of weaning was combined with curcumin administered from the end of weaning for the rest of the animals’ lifetime, intestinal adenoma numbers were reduced by 38%. The combination was not superior to intervention postweaning with curcumin alone. These results show that aspirin exerts chemopreventive activity in the ApcMin/+ mouse during tumour initiation/early promotion, while curcumin is efficacious when given at a later stage of carcinogenic progression. Thus, the results suggest that in this mouse model aspirin and curcumin act during different ‘windows’ of neoplastic development.
British Journal of Cancer (2003) 88, 1480 – 1483. doi:10.1038/sj.bjc.6600900 Keywords: ApcMin/+ mice; aspirin; curcumin; chemoprevention It has been estimated that over half of the Western population during adulthood only did not (Sansom et al, 2001). It is not develops benign adenomatous polyps during its lifetime, and that known whether aspirin retains its efficacy in this model when 10% of these tumours proceed to malignant colorectal carcinoma given only during embryogenesis and weaning, without being (Kinzler and Vogelstein, 1996). This realisation has engendered an present in the diet thereafter. Mechanistically curcumin shares intense search for efficacious chemopreventive intervention with aspirin the ability to interfere with levels of functional strategies using animal models of premalignant and malignant cyclooxygenase (COX) enzymes. While aspirin inhibits COX colorectal cancer. The ‘multiple intestinal neoplasia’ (ApcMin/+) enzyme activity (Vane, 1971), curcumin interferes with the mouse model of human familial adenomatous polyposis (Moser NFkB-mediated activation of COX-2 transcription (Plummer et al, et al, 1990) has been instrumental in the identification of several 1999). An attractive feature of curcumin is the fact that it fails to potential chemopreventive drug candidates, among them nonster- elicit detrimental gastrointestinal side effects associated with oidal anti-inflammatory drugs (NSAIDs), exemplified by sulindac traditional NSAIDs, such as aspirin. In the study described here, (Boolbol et al, 1996) and aspirin (Mahmoud et al, 1998), and the we wished to explore whether dietary aspirin and/or curcumin spice curcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-hepta- retard neoplastic development in the ApcMin/+ mouse when diene-3,5-dione (Mahmoud et al, 2000; Perkins et al, 2002).
administered in utero and during weaning, without being present Curcumin is the major yellow pigment extracted from turmeric, in the diet thereafter. Aspirin was found to be efficacious when the powdered rhizome of the herb Curcuma longa. Interestingly, administered in this way, but curcumin was inactive. Therefore, the evidence for the chemopreventive efficacy of aspirin in the hypothesis was tested that a combination of aspirin in utero ApcMin/+ mice, and similar models involving mutant Apc is and during weaning followed by curcumin postweaning results in ambiguous. In two studies in ApcMin/+ mice, aspirin suppressed additive or synergistic adenoma-suppressing activity, as this malignancy (Barnes and Lee, 1998; Mahmoud et al, 1998), while in regimen might exploit age-related differences in susceptibility of two others in ApcMin/+ and Apc1638N/+ mice it failed to show ApcMin/+ mice to the cancer-delaying effects of these agents.
efficacy (Williamson et al, 1999; Chiu et al, 2000). This discrepancyis probably related to differences in the aspirin regimen used inthese studies, a notion borne out by the recent finding that continual exposure of ApcMin/+ mice to aspirin from the point of conception onwards suppressed tumorigenesis, while exposure Experiments in mice were conducted as stipulated by the Animals(Scientific Procedures) Act 1986 Project Licence 80/1250 granted toLeicester University by the UK Home Office, and the experimental *Correspondence: Dr A Gescher; E-mail: ag15@le.ac.uk design was vetted and approved by the Leicester University Ethical Received 18 November 2002; revised 29 January 2003; accepted 18 Committee for Animal Experimentation. C57BL/6J male ApcMin/+ mice and C57Bl/6J female wild-type mice were mated to maintain Aspirin and curcumin in ApcMin/+ miceS Perkins et al the ApcMin/+ breeding colony. Tissue samples were obtained by ear punch and genotyped for Min/+ status by PCR and HindIII digestof the product as described previously (Luongo et al, 1994).
Administration of aspirin (0.05%) in utero and during weaning in Curcumin and aspirin were purchased from Apin Chemicals ApcMin/+ mice and maintaining mice on aspirin-free diet there- (Abingdon, UK) and Sigma (Poole, UK), respectively. The purity of after, reduced tumour burden in the small intestine by 21% curcumin was verified by HPLC analysis; this material contained (Figure 2). This result is consistent with the notion that the 3% desmethoxycurcumin. Aspirin or curcumin was blended into majority of adenomas in ApcMin/+ mice are fixed already either in RM3 high protein breeders diet (SDS, Witham, UK), using a utero or perinatally just after birth (Shoemaker et al, 1995; Ritland mechanical mixer to ensure uniform distribution, which was and Gendler, 1999) It suggests, for the first time, that interference confirmed by HPLC analysis. Breeding pairs were established and with tumour initiation and/or early promotion in ApcMin/+ mice fed RM3 maintenance diet or RM3 containing either 0.05% aspirin, can have a long-term beneficial consequence, even if the which translates into 75 mg kgÀ1 pd, or 0.2% curcumin, which chemopreventive stimulus is discontinued postweaning. A similar translates into 300 mg kgÀ1 pd. After 2 weeks, the females were reduction was observed in the colon, however overall colonic removed and maintained on their respective diets, until the adenoma burden was so low that the difference between exposed offspring were removed and genotyped at 3 weeks of age. At 30 and unexposed mice was not significant (result not shown). The days, the offspring with the Min/+ phenotype were divided into modest but significant reduction of intestinal adenoma burden by three intervention groups of eight to 10 animals (Figure 1): (i) mice aspirin is consistent with previous work according to which long- that received RM3 control diet, (ii) mice that received either term dietary administration of aspirin from conception onwards aspirin or curcumin in RM3 diet perinatally and during days 1 – 30, increased the survival of ApcMin/+ mice, while exposure during followed by RM3 diet omitting aspirin/curcumin to the end of the adulthood only did not (Sansom et al, 2001). The failure of aspirin experiment; (iii) mice that received aspirin perinatally and during to attenuate neoplastic development in ApcMin/+ mice, when days 1 – 30, followed by curcumin in RM3 diet from weaning to the administered postweaning only, has been demonstrated in at least end of the experiment. The early administration regimen will be three other studies (Williamson et al, 1999; Chiu et al, 2000; Reuter referred to in the following as ‘in utero and during weaning’, thelate regime as ‘postweaning’. An experiment, in which micereceived curcumin postweaning to the end of the experiment, hasbeen performed previously in this laboratory (Perkins et al, 2002)and was not repeated here to reduce animal usage. At 120 days,mice were killed by cardiac exsanguination under terminalhalothane anaesthesia. The gastrointestinal tract was removed,and multiplicity, location and size of adenomas were recorded as described previously (Perkins et al, 2002). Adenoma numbersvalues were subjected to statistical evaluation by ANOVA usingExcel and Minitab software packages (Microsoft Windows, 1997).
Statistical significance (Po0.05) was established by post hoc Tukey’s pairwise comparison. The haematocrit, the percentage of blood volume occupied by packed erythrocytes, was determined as described previously (Strumia et al, 1954) using blood samples collected and drawn by capillary force into heparinised micro- haematocrit tubes (75 mm, Richardson’s, Leicester, UK).
Effect on adenoma burden in the small intestine of ApcMin/+ mice of aspirin (‘asp’, 0.05% in the diet, open bar) or curcumin (‘curc’, 0.2%in the diet) administered in utero and during weaning (‘preweaning’, bar striped diagonally bottom left to top right), or of curcumin administered postweaning to the end of the lifetime (‘postweaning’, bar striped diagonallytop left to bottom right), or of the combination of aspirin in utero and during weaning followed by curcumin postweaning (black bar). Adenoma burden is expressed as percentage of number of adenomas in untreated mice, the number of mice used per group was eight to 10. The value for the effect of curcumin postweaning (bar striped diagonally top left to bottom right) was obtained previously (Perkins et al, 2002) and has beenincluded for comparison; this experiment was not repeated here to minimise animal usage. The results originate from three separate experiments, and number of intestinal adenomas in the control (untreated)groups were as follows: experiment described by open and black bars: Experimental design for the evaluation of the chemopreventive 132712, experiment described by bar diagonally striped bottom left to efficacy of aspirin (0.05%) or curcumin (0.2%) administered in the diet in top right: 117713, experiment described by bar striped diagonally top left utero and during weaning, or of curcumin from termination of weaning to to bottom right: 115712. The s.d.s of adenoma number values for the the end of the experiment, or of the combination of aspirin in utero and different interventions are 12% of the mean, or smaller. Asterisk indicates during weaning followed by curcumin postweaning. RM3 was the control that the number of adenomas is significantly different from that in control diet. The study was terminated after 120 days. For details of animals and (untreated) animals (Po0.05). For details of animals and treatments and treatments see Materials and Methods.
statistical evaluation, see Materials and Methods.
British Journal of Cancer (2003) 88(9), 1480 – 1483 et al, 2002). In contrast, there are reports that document kidneys and/or undergoes phase II drug metabolism (Needs and convincingly the ability of two NSAIDs other than aspirin, Brooks, 1985). Furthermore, salicylate generated by hydrolysis of piroxicam (Ritland and Gendler, 1999) and celecoxib (Jacoby aspirin reaches breast milk readily (Findlay et al, 1981). When et al, 2000b), to decrease the number of established polyps and administered to the mother, salicylates are rapidly transferred to to prevent the development of nascent ones, when they the fetus (Schoenfeld et al, 1992). As aspirin has a short half-life, are administered at a late stage during the lifetime of ApcMin/+ only a small amount of unmetabolised drug reaches the fetus, which is therefore exposed mainly to its metabolite salicylate.
Detailed analysis of the results obtained for aspirin reveals that Compared to the adult organism, the fetus has reduced abilities of administration in utero and during weaning reduced the number salicylate plasma protein binding, biotransformation and drug of middle-sized adenomas, those of 1 – 3 mm diameter, in both the elimination. Therefore, fetusses and newborns whose mothers middle and distal regions of the small intestine (Figure 3). The received aspirin before delivery may have plasma concentrations decrease in tumour size intimates that aspirin delays adenoma of free salicylate up to four times higher than those of their development, rather then totally suppressing the emergence of a mothers (Schoenfeld et al, 1992). The finding that aspirin exerted subset of adenomas. The efficacy of aspirin when it is administered chemopreventive efficacy when administered in utero and during in utero and during weaning only suggests that in the ApcMin/+ weaning is consistent with these pharmacokinetic considerations, mouse there is a ‘window of opportunity’ for preventive in that efficacy was probably the consequence of efficacious levels intervention using aspirin, and this window occurs in very young of salicylate in the mother’s milk and the embryonic blood and mice. A similar window of susceptibility allowing regulation of tissues. In contrast, the absorption of curcumin is poor and its tumour development in ApcMin/+ mice has been suggested by systemic availability is extremely low in all species in which it has results of experiments in which the effect of the carcinogen N- thus far been tested (Ireson et al, 2001). Therefore, when curcumin ethyl-N-nitrososurea on the formation of crypts and adenomas was was administered in utero and during weaning in ApcMin/+ mice, levels of drug which reached the maternal blood and milk and the In contrast to aspirin, dietary curcumin (0.2%) administered fetal organism were conceivably insufficient to elicit chemopre- in utero and during weaning only, failed to affect adenoma number (Figure 2). This finding suggests that high preventive efficacy at Sequential administration in ApcMin/+ mice of firstly aspirin the stage of tumour initiation/early promotion is not a generic in utero and during weaning and secondly curcumin given feature of all agents that target COX enzymes. In contrast, postweaning for the remainder of the animals’ lifetime decreased curcumin administered later, that is, from the end of weaning mean tumour burden slightly, but not significantly, more than the for the lifetime, reduced intestinal adenoma burden in ApcMin/+ aspirin-only regimen (Figure 2). The extent of adenoma reduction mice by 39%, compared to untreated mice (Figure 2, reference by the combination was also not superior to intervention with curcumin alone administered postweaning (Figure 2). Analysis of These results warrant interpretation in terms of our knowledge tumour distribution (Figure 3) shows that sequential intervention of the pharmacokinetics of aspirin and curcumin. Aspirin is with aspirin followed by curcumin significantly reduced the efficiently absorbed, rapidly distributed and swiftly hydrolysed in number of small adenomas in the proximal and distal regions the biophase to salicylate, which in turn is eliminated via the and of middle-sized adenomas in the middle and distal regions, Adenoma multiplicity (differential from control) Effect of dietary aspirin (0.05%) administered in utero and during weaning (bars 1) or of the combination (bars 2) of aspirin, given as above, with dietary curcumin (0.2%), administered postweaning to the end of the experiment, on multiplicity of small (o1 mm diameter, open bars) medium size (1 –3 mm, hatched bars) or large (43 mm, closed bars) adenomas in the proximal (A), middle (B), distal (C) or colonic (D) sections of the intestine of ApcMin/+mice. Results are expressed as mean number of adenomas over or below mean adenoma numbers in control (untreated) ApcMin/+ mice. Number of miceper group was eight to 10. Asterisk indicates that the number of adenomas in that segment was significantly different from that in the respective segment incontrol animals (Po0.05). For details of animals and treatments and statistical evaluation see, Materials and Methods.
British Journal of Cancer (2003) 88(9), 1480 – 1483 Aspirin and curcumin in ApcMin/+ miceS Perkins et al which is comparable to the efficacy characteristics of curcumin What is the corollary of these results for cancer chemoprevention in humans? In utero administration of drugs is obviously not a Even though aspirin and curcumin are considered to act feasible intervention strategy in humans. Nevertheless, the proof of via similar modes of action by decreasing levels of active principle study described here allows the conclusion that that there COX enzymes, there are clear differences between them seem to be different ‘windows of susceptibility’ during preneoplastic as reflected by the age-related discrepancy in susceptibility and neoplastic development, in which agents exert their preventive of ApcMin/+ mice towards drug activity. On the one hand, aspirin activities differentially, at least in the ApcMin+ mouse. Applied to and curcumin seem to exert optimal adenoma-retarding activity humans this realisation adds another layer of complexity to the at different stages of the lifetime of ApcMin/+ mice, aspirin early design optimisation of intervention trials using combinations of and curcumin late; on the other hand, we failed to observe agents. Multiagent chemoprevention strategies in ApcMin/+ mice additivity or synergy when both agents were administered which have been efficacious are combinations of piroxicam with sequentially. Together these findings are consistent with the difluoromethylornithine (Jacoby et al, 2000a), and of sulindac with notion that in this mouse model aspirin and curcumin exert their the epidermal growth factor receptor kinase inhibitor EKI-569 activities probably on the same cells, but within different (Torrance et al, 2000) or with tea polyphenols (Orner et al, 2002). A better delineation of the developmental window which permits The administration regimens involving aspirin in utero and optimal efficacy for each agent might help to improve the use of during weaning alone or in combination prior to curcumin had no combination chemoprevention strategies in humans.
detrimental effect on propensity towards gastrointestinal bleeding,as reflected by the haematocrit (results not shown), nor did theycause gastric erosion and loss of mucosal integrity, as adjudged by macroscopic inspection. These side effects are often associatedwith long-term administration of NSAIDs.
We thank the MRC for a postgraduate studentship (to SP).
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British Journal of Cancer (2003) 88(9), 1480 – 1483

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