COXIndependent Actions on Cell Function

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The most convincing evidence for prostaglandin-independent though biologically significant actions of salicylates is their biosynthesis by plants. Salicy-lates are natural plant constituents and part of a defense system that protects them from injury by exogenous noxes such as bacteria or viruses. Salicylate generation increases plant resistance and can be substantially upregulated at the transcriptional level in response to injury. The failure to do so, for example, after genetic manipulation, results in severe damage or cell death. Plants only can synthesize (polyunsaturated) fatty acids up to an 18 hydrocarbon (C18) backbone. Thus, neither arachidonic acid (C20) norprostaglandins or other mediators derived from arachidonic acid peroxidation can be generated. However, plants can synthesize jasmonic acid via a lipid peroxidation pathway that has many structural and functional similarities to prostaglan-dins. Thus, generation of salicylates in plants represents a prostaglandin-independent protective mechanism that increases plant resistance and has provided several innovative approaches for the development of insecticides and pest management.

Aspirin and salicylate exhibit a broad spectrum of pharmacological actions on cell function [142] that is probably not completely elucidated yet. The transacetylation and nontransacetylation-related actions of aspirin are nonselective and nonspecific. Transacetylations may occur at any appropriate molecular site in any macromolecule, most notably plasma albumin and hemoglobin [102] as well as DNA [143], whereas salicylic acid will accumulate inside cell membranes, including those of mitochondria, with subsequent alterations in cell signaling and energy metabolism.

One of the earliest studies demonstrating COX-independent actions of aspirin on inflammatory cells came from Gerald Weissmann's group. They showed that aspirin and salicylate were about equipotent inhibitors of neutrophil aggregation and Ca2+ entry (signaling) whereas only aspirin but not salicylate inhibited platelet aggregation and thromboxane formation (signaling) (Figure 2.15). Since neutrophils do not synthesize prostaglandins, this finding suggested that aspirin and salicylate inhibit neutrophil reactions through mechanisms independent of the prostaglandin system. Later works showed a disturbed assembly of heterotrimeric G proteins within the lipid bilayer of cell membranes by salicylates. This suggests that membrane effects of salicylate, possibly related to its particular physicochem-ical properties (Section 2.2.3), might interfere with transmembrane signal transduction. These actions of salicylates require higher concentrations than the transacetylation reaction. However, the concentrations of 1-3 mM - used in this particular study - were still within the therapeutic range obtained with anti-inflammatory doses of aspirin [144, 145].

The modulation of enzymes of the cell energy metabolism and, most interestingly, heat-shock proteins and chaperones [146-148], probably, is

Figure 2.15 Different actions of aspirin and sodium salicylate on human platelets and granulocytes in vitro. Stimulation of platelet aggregation by arachidonic acid was blocked after pretreatment with aspirin but remained unchanged after pretreatment with an equimolar concentration of Na salicylate. In contrast, stimulation of neutrophil aggregation by the chemoattractant of MLP was inhibited to a similar extent by both aspirin and Na salicylate. Arrows mark the addition of the agonists (modified after [144]).

Figure 2.15 Different actions of aspirin and sodium salicylate on human platelets and granulocytes in vitro. Stimulation of platelet aggregation by arachidonic acid was blocked after pretreatment with aspirin but remained unchanged after pretreatment with an equimolar concentration of Na salicylate. In contrast, stimulation of neutrophil aggregation by the chemoattractant of MLP was inhibited to a similar extent by both aspirin and Na salicylate. Arrows mark the addition of the agonists (modified after [144]).

involved in regulatory actions of aspirin on enzymatic processes in inflammation, immune responses, and tumor defense. All of these actions are salicylate mediated.

Salicylate concentrations, necessary to exert analgesic/anti-inflammatory effects, are substantially higher (about 150-450 mg/ml or 1-3mM) than those necessary to inhibit prostaglandin biosynthesis. This either suggests additional sites of action or indicates that enhanced prostaglan-din production is rather an epiphenomenon than a causal factor of these disorders. After cell stimulation by inflammatory cytokines or tumor promoters, salicylates interact with cellular signal generation and signal transduction at both the transcriptional and posttranscriptional levels. Transcription factors and kinases appear to be the central cellular target and cytokines a major class of mediators involved [149, 150]. The functional consequences ofthese multiple activities of salicylates for inflammation, pain, and fever are discussed in more detail in Section 2.3.2, the consequences for cell proliferation with particular relevance to malignancy in Section 2.3.3. This section deals with the mechanistic aspect ofthese activities.

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