Aspirin and Malignancies
The understanding ofthe biological steps associated with the transformation of an apparently normal diploid somatic cell into a malignant tumor cell is one of the most challenging issues in cell biology. Tumor cells digest the intercellular matrix, migrate, and proliferate. They lose control by body defense mechanisms and become potentially immortal by defective apoptosis. Aspirin has been brought into connection with this issue after the finding that tumor growth and malignancy can be modulated by prostaglandins  and the pioneering epidemiological study by Kunethat regular long-term aspirin intake significantly reduces the risk of colorectal cancer (Section 4.3.1). These and other data indicate a significant therapeutic potential of aspirin in che-moprevention of malignancies. Mechanistically, this involves not only the interaction with prosta-glandin-mediated immunosuppression of immu-nocompetent cells but also nonprostaglandin-related actions [390-392], including intracellular accumulation of free arachidonate as an apoptotic signal after prevention of its metabolic conversion .
More recent data in different experimental setups as well as an improved knowledge of tumor etiology increasingly suggest that antitumor effects and inhibition of prostaglandin biosynthesis by aspirin and other NSAIDs, most notably selective inhibitors of COX-2, are separable processes . Specifically, conversion of a normal diploid cell with a limited life span into a cell at a state of immortality as result of defective apoptosis appears to be rather determined by genetic factors such as an insufficient expression or function of suppressor genes. However, prostaglandins might rather sustain and enhance tumor growth and malignancy. In addition, aspirin at the high doses used in many experimental studies on carcinogenesis, that is, 5-10 mM (cf. ) is toxic or even lethal to normal cells. At these concentrations, there are marked disturbances in cell energy metabolism due to uncoupling of oxidative phosphorylation (Section 2.2.3).
These metabolic actions are presumably particularly effective in cells with abnormally high metabolic turnover and proliferation rates, such as tumor cells.
Among the different localizations of malignant tumors, the gastrointestinal system has found particular attention. This is partially because of the fact that this is the organ system with most available and convincing epidemiological data on possible benefits of aspirin as a tumor preventive drug. This is indirectly supported by prospective randomized trials in high-risk populations, such as individuals with adenomatosis polyposis coli (APC) with defective APC tumor suppressor genes (Section 4.3.1). Accordingly, intestinal tumor cells are frequently used models to study actions of aspirin and NSAIDs in experimental carcinogenesis and have provided important information regarding the action ofaspirin on tumorigenesis and tumor growth. Because of this, this section is focused onthe effects ofaspirin on colorectal cancer. However, this does not exclude similar actions of aspirin in other malignancies.
Aspirin-related actions on tumor cells involve changes in not only prostaglandin formation and COX-2 expression but also COX-independent mechanisms, most notably those that control apopto-sis. These processes are not necessarily independent of each other. However, they will be discussed separately because the actions of aspirin and NSAIDs may not rely on only one mechanism. An overview on possible targets ofaspirin as a chemo-preventive drug is shown in Table 2.13.
Aspirin might affect cyclooxygenase(s) at different levels: inhibition of COX-2 expression, by interfering with tumor promoters that activate the gene; modulation of COX- 2 activity and product formation (Section 2.2.2) as well as activation of (co)carcino-gens and formation of malondialdehyde (MDA).
Expression of COX-2 In biopsy samples taken from colorectal mucosa of healthy men, there is only expression ofCOX-1 protein but no expression
Table 2.13 Possible mechanisms of anticancerogenic actions of aspirin in (colon) carcinoma cells.
Inhibition of COX-2 gene expression by interaction with C/EBP-b (Section 2.2.2)
Inhibition of COX-2-dependent PGE2 formation Antagonism of PGE2-mediated immunosuppression. Possibly involving enhanced cAMP responses by upregulating cAMP-stimulating (EP2, EP4) and down-regulating cAMP reducing (EP3) receptors
Inhibition of COX-2/peroxidase-mediated of (co)carcinogens
Accumulation of free intracellular arachidonate (generation of ceramide?)
Modulation of oncogen-induced expression of transcription factors (NFkB; AP-1, others)
Interaction with DNA mismatch-repair genes
Energy depletion of (tumor) cells by uncoupling of oxidative phosphorylation (Section 2.2.3)
of COX-2. However, COX-2 becomes transcriptionally upregulated in human colorectal adenomas and adenocarcinomas [396-399], probably as a consequence of loss of the adenomatous polyposis coli gene function  (Section 4.3.1). There is a relationship between the degree of malignancy (lymph node metastases, tumor size) and COX-2 expression [401-403]. Accordingly, COX-2 expression was found in 40-50% of premalignant adenomas and in 80-90% of colorectal carcinomas . This suggests that at least the proliferative and metastatic potential of tumor cells is modified by COX-2-derived products. Accordingly, intestinal epithelial cells, made to overexpress COX-2 consti-tutively, change their phenotype. They become more adhesive to the extracellular matrix and increasingly resistant against apoptosis . Both findings are consistent with a COX-2-mediated increased tumorigenic potential. Accordingly, selective inhibition of COX-2 inhibits tumor growth  whereas exogenous administration of PGE2 has the opposite effect .
Both aspirin and salicylate inhibit tumor-promoter-induced expression of COX-2 protein at the level of transcription (Section2.2.1). Thus, one might expect that salicylate contributes to or even mediates the antitumor effects of aspirin. However, aspirin - in contrast to salicylate - is additionally able to acetylate COX-2 with subsequent generation of 15-(R)-HETE, a precursor for aspirin-triggered lipoxin. In addition to its antiinflammatory potency (Section 2.3.2), ATL also inhibits cell proliferation of tumor cells .
COX-2-Related Product Formation Several products can be generated by COX-2 and/or the related peroxidase activity that have a relation to malignancy: (i) prostaglandins, in particular, PGE2, (ii) peroxy radicals that might activate (co)car-cinogens, and (iii) malondialdehyde, a direct mutagen. Finally, the expression of prostaglandin EP receptors is changed in colorectal carcinomas, and this might also be relevant to aspirin treatment.
Aspirin and Prostaglandins The concentrations of E-type prostaglandins in healthy colorectal mucosa are very low, amounting to about 0.1-0.4 ng PGE2 per mg protein . In human intestinal biopsies, only PGE2 and no other COX products were significantly increased in canceromatous tissue . Quantitatively, the tissue levels of PGE2 were three- and fourfold higher as compared with apparently healthy colon tissueofthe same patients . In addition to malignant colonic epithelial cells, tissue macrophages and fibroblasts are natural sources of PGE2 , suggesting both autocrine and paracrine actions of PGE2 on tumor cells. Interestingly, similar changes have also been found in adenomatosis polyposis coli, a colon cancer-prone state (Section 4.3.1). E-type prostaglandins act immunosuppressive to cells of tumor defense and, in addition, stimulate growth of isolated tumor cells . PGE-mediated suppression of cellular immune reactions was also found in vivo in patients, suffering from colorectal carcinoma [390, 415].
Aspirin at daily doses of 325 mg inhibits PGE2 formation in human colonic mucosa cells by more than 50%. The generation of leukotrienes (LTB4) remains unaffected. Higher doses, that is, 650 mg/ day aspirin, not only produce stronger inhibition of PGE2, that is, by about 80-90%, but are also associated with more side effects .
Activation of (Co)carcinogens In addition to generating prostaglandins, COX-2  might also initiate carcinogenesis by metabolic activation of carcinogens to DNA-binding forms via the broad-spectrum peroxidase activity of the PGH-2-synthase complex. Examples are polycyclic aromatic hydrocarbons, phenols, and other substrates of redox activation. Aspirin has been shown to inhibit con-centration-dependently on the activation of one of these enzymes (phenolsulfotransferase) in colonic mucosa at micromolar concentrations . The efficacy of aspirin to prevent carcinogenesis by COX-2-dependent modification of carcinogens has also been shown in vivo, using dimethylhydrazine as carcinogen.
Malondialdehyde Another putative cancerogenic pathway is the generation of malondialdehyde. MDA is a directly acting mutagen and reacts with DNA to form adducts to deoxyguanosine and deoxy-adenosine. MDA is generated enzymatically via the COX-2 pathway of arachidonic acid peroxidation, where about 50% of PGH2 are enzymatically converted to MDA by thromboxane synthase. MDA may also be formed by nonenzymatic lipid peroxidation that is not aspirin sensitive. So far, there is no evidence that aspirin modifies MDA-related mutagenesis.
Prostaglandin Receptors Cellular effects of PGE2 are mediated via specific EP receptors (EP1-4). EP2 and EP4 receptor stimulation increases tissue cAMP levels whereas EP3 receptor stimulation has the opposite effect. EP3 receptor mRNA has recently been found to be markedly, by more than 70%, downregulated in human adenocarcinomas as compared with adjacent normal colon mucosa whereas the mRNA of the functional antagonist EP2 was upregulated . Inhuman colon cancer cell lines, EP1, EP2, and EP4 receptor mRNA were detected in almost all of them whereas mRNA for EP3 was only rarely found. These data and animal studies collectively suggest that upregulation of cAMP-elevating EP2 and EP4 and downregulation of the cAMP-reducing EP3 may be involved in colon carcinogenesis [421, 420]. Aspirin might interact with the expression of these receptors and their distal signaling via modulation ofcytokine release. However, this issue has not been studied in more detail so far.
18.104.22.168 Nonprostaglandin-Related Antitumor Actions of Aspirin
Apoptosis and Cell Cycle Control Aspirin and other NSAIDs cause apoptosis and alter the expression of cell cycle regulatory genes in carcinoma cells [422,423,436]. Salicylates have been shown in vitro to block the cell cycle in the G0-G1 phase in colo-rectal tumor cell lines, thereby preventing the entry of cells into the mitotic program . The sensi
Colonic carcinogenesis was induced in rats after single treatment with dimethylhydrazine. Tumor density and proliferation rate were determined. In addition, to PGE2 tissue levels of cAMP levels were measured as a marker of postreceptor PGE2 signaling. Animals were treated with aspirin according to different protocols at a dose that reduced colonic PGE2 formation ex vivo by 95%. The duration of the study was 36 weeks.
The incidence of colonic adenocarcinomas was reduced by 60% in rats receiving aspirin for 1 week before and 1 week after administration of the carcinogen. Aspirin had no effect on tumor incidence when the treatment was started only 4 weeks after carcinogen exposure and continued until the end of the experiment, that is, 36 weeks. Early treatment with aspirin reduced both basal and arachidonate stimulated generation of the active dimethylhydrazine metabolite, methylazoxymethanol, by colonic mucosa homogenates.
The conclusion was that suppression of dimethylhy-drazine-induced colonic carcinoma by aspirin involves an altered metabolic activation of the carcinogen by COX-2-dependent cooxidation and that this effect may not be linked to the - also detectable - inhibition to colonic PGE2 synthesis .
tivity of malignant tumor cells to salicylates was markedly higher than that of nonmalignant adenoma cells. These and other data support the interesting hypothesis that aspirin and NSAIDs can possibly substitute for the physiological function of the (missing) APC tumor suppressor gene in colorectal cancer cells by inducing apoptosis.
Treatment with prostaglandins did not reverse the proapoptotic effects of aspirin and other NSAIDs, suggesting that they were independent of prostaglandin formation . Moreover, structural analogues of NSAIDs that were non-COX inhibitors did induce the same anticarcinogenic changes in cell cycle and apoptosis . Finally, aspirin also protected from tumor growth and stimulates apoptosis in COX-2 knockout mice [390, 424]. All of these data suggest that at least part of aspirin and NSAID-induced apoptosis in colon cancer cells is independent ofprostaglandin formation. Alternatively, accumulation of arachi-donic acid after COX inhibition will cause buildup of ceramide that sensitizes colon carcinoma cells to apoptosis  in addition to generating an apo-ptotic signal by its own [426, 393]. In addition, proapoptotic fatty acid peroxidation products might be generated, such as the 15-lipoxygenase products of linoleic acid .
Actions on DNA There are two different and separate mechanisms by which drugs can affect tumorigenesis via DNA modulations: (i) interactions with gene regulation, most notably transcription factors of tumor promoting or tumor suppressor genes and (ii) interaction with (disturbed) DNA-repair mechanisms. Defective DNA repair will allow for nonselected amplification of defective genes because of prevention of their degradation. There are many experimental data onthis issue. However, they are often derived from immortal tumor cell lines in vitro and might not be directly transferable to malignancy in vivo. In many of these experiments, concentrations of aspirin in the medium-to-high millimolar range have been used, being toxic or even fatal also to nontumor cells.
Transcription Factors One of the primary actions exerted by oncogens is the modulation of gene transcription by interacting with transcription factors. The nuclear factor KB/RelA family of transcription factors (NFKB/RelA) is one of them and regulates the expression of numerous genes involved in the control of not only immune and inflammatory responses (Section 2.2.2) but also apoptosis and cell survival. NFkB acts either as a regulator ofthe apoptotic program for induction of apoptosis or, more commonly, as its inhibitor . These disparate effects depend on the stimulus, cell type, and intracellular signaling pathways, eventually resulting in diverse target gene specificity and the more distal signaling pathways and their targets . Aspirin causes activation of NFkB by signal-specific IkB degradation in colorectal carcinoma cell lines [429, 430]. This reaction was independent of the tumor suppressor gene p53 and other markers of genomic instability. However, as already seen with the role of NFkB in inflammation, salicylate treatment for 16 h with 1-10 mM aspirin in vitro is necessary to obtain this effect. These levels, specifically in terms of free salicylate, can probably not be obtained in vivo and also not maintained for such a long time period.
Another aspirin-sensitive transcription factor is activator protein-1 (AP-1) . The inhibition by aspirin of this factor also required millimolar concentrations and was paralleled by a fall in intracellular pH. This strongly suggests a relationship of AP-1 inhibition to the protonophoric, that is, metabolic, actions of salicylates (Section 2.2.3).
The most interesting finding was that pretreatment with aspirin might downregulate the expression of the apoptosis gene Bcl-2 in human colorectal carcinoma cells via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Pretreatment by aspirin (1 mM) of TRAIL-resistant cancer cells resulted in sensitization of these cells and augmented TRAIL-induced apoptotic death. This action required 12 h of pretreatment with aspirin and was related to down-regulation of Bcl-2 and decrease of the mitochondrial membrane potential.
The conclusion was that aspirin might enhance apoptosis in tumor cells by promotion of TRAIL cytotoxicity .
Thus, there are several tumor-promoting mechanisms at the level of gene transcription that could be modified by aspirin and might be involved in its tumor suppressor action in colorectal carcinoma. Upregulation of trefoil factor family (TFF) peptides, specifically TFF2, might be another mechanism involved in the chemopreventive action of aspirin in gastric adenocarcinoma cell lines .
DNA Injury and Repair Mismatch repair genes and proteins are important to correct for DNA instability by removing defective genes. Aspirin treatment of cultured colorectal cancer cells for 12 weeks markedly reduced DNA instability in cells genetically deficient for a subset of mismatch repair genes. It was suggested that aspirin induces a genetic selection for DNA stability that might be important for preventing hereditary nonpolyposis colorectal cancer . However, the duration of treatment was long (over weeks) and the effective aspirin concentrations high (>1 mM). Others have shown that aspirin inhibits oxidative DNA strand breaks, mediated by reactive oxygen species . Thus, aspirin might well modify the structure of DNA. Possibly these actions are related to the long known acetylation of DNA , the biological significance, however, ofthese alterations for carci-nogenesis in vivo remains to be determined.
Independent of the rather specific actions on cellular signaling pathways, aspirin might also exert nonspecific actions on cell function, specifically at higher concentrations in vitro. This includes actions on cellular energy metabolism, that is, uncoupling of oxidative phosphorylation and disturbed cellular metabolism by impaired mitoch-ondrial b-oxidation of long-chain fatty acids (Section 2.2.3). Both reactions are likely to be particularly effective in proliferating cells with increased energy requirements, that is, malignant tumor cells. It is surprising that their possible contribution to antitumor effects of aspirin has apparently not been studied in more detail so far. One possible explanation is that the basic research on aspirin-related changes in energy metabolism has been done - and completed - many years before an antitumor action of aspirin was described. Researchers also possibly found changes in gene transcription more attractive than nonspecific inhibition of kinases because of lack of ATP.
In addition to antithrombotic, anti-inflammatory, and analgesic effects, aspirin also modifies growth and proliferation of malignant tumors. An effective chemoprevention in malignant tumors has been most extensively studied - and shown - in colorectal carcinomas (Section 4.3.1). Possible mechanistic explanations are interactions with not only an upregulated COX-2, by oncogenes, and COX-2-dependent product formation but also COX-2-independent mechanisms.
There is significant transcriptional upregula-tion of COX-2 in colorectal cancer as well as adenomatous polyposis coli associated with a marked increase in prostaglandin (PGE2) formation. These changes appear to be associated with a differential regulation of EP receptors and, as a net effect, result in elevated tissue cAMP levels. Aspirin not only reduces PGE2 formation but also interacts with tumor-promoter-induced COX-2 expression and other COX-2 activities, specifically, the redox activation of (co)carcinogens.
In addition to interactions with COX-2, aspirin might also modify COX-independent pathways of cell signaling and survival. This includes modification of transcription factors (NFkB, AP-1) and interactions with mismatch repair genes. These actions are also seen in COX-2 knockout animals. The effects of aspirin are shared by salicylate. However, they require medium to high millimolar concentrations in vitro. At these concentrations, salicylates uncouple oxidative phosphorylation and might cause metabolic failure of cells, in particular, cells with increased turnover and energy metabolism, such as tumor cells.
Overall, the mechanisms of anticarcinogenic actions of aspirin are probably complex and in many important aspects poorlyunderstood. How ever, the 50% reduced risk of colorectal cancer after long-term treatment with aspirin, according to clinical trials (Section 4.3.1), is an impressive finding and should stimulate basic research to improve the understanding of its biological background.
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