Many natural compounds I discuss have the potential to inhibit aspects of the immune system. Although none of these is generally considered a primary immunosup-pressive agent, each can produce immunosuppression as a secondary effect, at least under some circumstances. Natural compounds can induce immunosuppression in many ways, such as by reducing signal transduction (immune cells need signal transduction to function), reducing NF-xB activity, histamine release, vascular permeability, and immune cell migration, as well as by causing anti-inflammatory effects. The most potent anti-inflammatory compounds tend to be those that reduce production of PGE2 or other inflammatory pros-taglandins or leukotrienes. Taking all of these actions into account, we can see that most compounds included in this book have the potential to contribute to an immu-nosuppressive effect; however, earlier in this chapter we also saw that most could also contribute to a stimulatory effect. What is the overall effect of combinations on the immune system and are some compounds are incompatible with others? Based on the information below, it would seem that the compounds discussed in this book are compatible and that combinations of them will generally facilitate an immune response and are desirable to use.
Any immunosuppressive effects these compounds may produce do not appear to interfere with their ability to inhibit cancer progression in vivo, as attested to by the many successful animal antitumor studies cited in Part III. It is likely, in fact, that most of these compounds, at concentrations applicable to humans, produce relatively mild effects on the immune system in comparison to their effects on cancer. Because cancer cells rely on such abnormal and excessive signals to function, they are probably more susceptible than immune or other normal cells to compounds that inhibit signal transduc-tion and other events that rely on signal transduction (for example, NF-kB activity and cell migration). As an analogy, aspirin has a marked effect on body temperature when the temperature is abnormally high (in fever), but relatively little effect when it is normal. In the same way, it is reasonable to suppose that these natural compounds will generally have more effect on the abnormal cellular activities found in cancer cells than they do on the normal activities found in immune or other healthy cells.
Concurrent use of immune stimulants and potential immunosuppressive compounds also seems compatible in that some of the latter actually increase the immune response. For example, although inflammation is part of the immune response, it can hinder the response when it is excessive. This immunosuppressive effect is largely due to excessive production of PGE2, although other factors may play a role. Since most anti-inflammatory compounds act by reducing PGE2 production, they have the potential to increase immune cell activity. Indeed, a recent review on impediments to successful immuno-therapy emphasized that immunotherapy is unlikely to be effective unless methods of immune escape by cancer cells, such as the production of PGE2 and other immu-nosuppressive compounds, are addressed.88 Furthermore, one mouse study reported that a combination of IL-2 and ibuprofen, an inhibitor of prostaglandin synthesis, was more effective in inhibiting metastasis of transplanted breast cancer cells than either agent alone.89
Note that non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, which inhibit prostaglandin synthesis and reduce inflammation, are not necessarily contraindicated in patients with infections, even though these patients require an effective immune system. Indeed, some NSAIDs can assist rodents to overcome some types of bacterial infections, especially chronic ones.90-93, a Moreover, the beneficial effect produced by NSAIDs against infection can be increased by administering immune-stimulating cyto-kines like interferons.94
Turning again to natural inhibitors of NF-kB, these compounds reduce inflammation and TNF production and in so doing may cause immunosuppression, but they also tend to inhibit PGE2 production and thus may in-
a In some cases, acute bacterial infections can be made worse by NSAIDs, since these drugs do reduce the initial immune response.
crease immune activity. Consider too the parallels between cancer treatment and treatment of patients with the HIV virus. Both diseases are driven by excessive NF-kB activity (although one could argue this is more true for HIV). Also, both diseases are associated with excessive ROS production, inflammation, and immuno-suppression.95 What is interesting is that inhibitors of NF-kB activity show promise in HIV treatment, in spite of the fact these patients are immunosuppressed.96,97 (In this case, NF-kB inhibitors serve to reduce rather than cause immunosuppression.) It seems possible that inhibitors of NF-kB could also be used in cancer patients without causing significant immunosuppression.
We can now identify some of the natural compounds with potential to cause immunosuppression. Inhibitors of signal transduction were discussed in Chapter 4; inhibitors of NF-kB activity were listed in Tables 5.1 and 5.2; those of PGE2 production, histamine release, and increased vascular permeability in Chapter 8; and inhibitors of cell motility were listed in Table 9.3. Of these, we discuss flavonoids and EPA in more detail, since their use is important to this book and their immunosup-pressive effects have received more study.
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