The Effects of Eicosanoid Inhibitors on Tumor Cell Arachidonic Acid (and Metabolite) Uptake, Release and Metabolism

Abstract

Arachidonic acid (AA) metabolites (eicosanoids), in particular lipoxygenase (Lox) products, have been implicated in several biological events believed to play a major role in the growth and metastasis of tumor cells (Powles et al. 1982). These include tumor growth, the release of lysosomal enzymes from tumor cells to initiate invasion, the chemotactic migration of tumor cells in response to stimuli and the adherence of tumor cells to biologically relevant substrata. Lox products may also augment platelet aggregation, which is believed to facilitate tumor cell transport and/or attachment. Attempts to alter the above mentioned tumor cell activities by pharmacological regulation of eicosanoid synthesis have led to many conflicting reports. This may be due, in part, to incomplete knowledge of the actions of the inhibitors used. We have found a dramatic lack of correlation between microsomal and whole cell inhibitor studies, especially with respect to Lox inhibition. Therefore, we began a closer study of the effects of eicosanoid inhibitors on three levels of eicosanoid regulation (Irvine 1982). The first level, substrate regulation, includes the uptake and release of AA from the phospholipid (PL) and triglyceride (TG) storage pools and the binding and release of this fatty acid by arachidonyl-specific and nonspecific intracellular binding proteins. The second level is direct interaction with the enzymes or cofactors required for optimal enzymatic activity. The third type of regulation is at the product level, i.e., influencing the fate of the eicosanoids after they are synthesized.