Effects of Taxol on Gene Expression: An Inducible Prostaglandin Endoperoxide Synthase
Gorman, Robert R., III
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Taxol is a potent, microtubule-stabilizing, antineoplastic drug that has demonstrated encouraging efficacy in clinical trials. Unfortunately, many patients receiving the drug experience significant toxicities, including hypersensitivity reactions and cardio- and neurotoxicity. Taxol mimics LPS induction for a number of genes, specifically those encoding proteins which regulate macrophage activation and tumoricidal activity. Prostaglandin endoperoxide synthase, known more commonly as cyclooxygenase (COX), is the rate-limiting enzyme in the biosynthesis of prostaglandins and thromboxanes from arachidonic acid. The enzyme exists in two isoforms, the constitutive COX I and the inducible COX II. COX II is induced by inflammatory mediators such as lipopolysaccharide (LPS) and interleukin-1 (IL-1). This study investigates the possibility that taxol induces COX II gene expression. Total RNA was isolated from an HL-60 cell line, both from undifferentiated cells and from cells differentiated to a macrophage-like phenotype with phorbol ester. COX IT mRNA expression in control cells and taxol-treated cells was analyzed using the reverse transcriptase-polymerase chain reaction. For the undifferentiated group, both control and taxol-treated cells yielded an equivalent COX II signal after 2 hr and 4 hr incubation, but lost those signals after 12 hr. For the differentiated group, control cells yielded a signal only after 4 hr incubation. Treated cells yielded a signal after 12 hr taxol incubation, and this signal was stronger than that for the control group. These results are consistent with an induction of the COX IT enzyme by taxol. This provides insight into taxols toxicities and allows for better treatment of those toxicities, either through the administration of less toxic taxol analogs or via COX II-specific inhibitors.