Structure-activity study on the actions of taxol and related taxanes on primary cultures of adrenal medullary cells

Abstract

Taxol is a natural plant product which has antimitotic activity. It is currently being investigated for use both as a cancer chemotherapy agent and as a tool to investigate microtubule involvement with various cellular functions. In the studies reported here, the actions of taxol on cultured adrenal medullary cells are compared to those of two other taxanes, baccatin III and 19-hydroxybaccatin III, which are structurally similar but lacking a bulky ester linkage at the C13 position. Unlike taxol, baccatin III and 19-hydroxybaccatin III have little or no known actions on mammalian microtubules. These studies were designed 1) to establish structural requirements for taxol's effects on adrenal cells and 2) to investigate whether the effects of taxol on adrenal cells involve microtubules. The effects of taxol on basal catecholamine release, on nicotinic receptor-stimulated catecholamine release and on the adrenal microtubule network are quantitatively and qualitatively different from those of baccatin III and 19-hydroxybaccatin III. These results suggest that esterification of taxol at position C13 is important in taxol's inhibitory actions on nicotinic receptor-stimulated catecholamine release. Similar structure requirements have been reported for taxol's actions on microtubules. Catecholamine release stimulated through activation of nicotinic receptors is much more sensitive to the inhibitory actions of taxol than is release stimulated by other secretagogues. Finally, a direct effect of taxol on the adrenal microtubular network was demonstrated using treatment conditions which are similar to those used to interfere with nicotinic receptor function. The studies reported here offer further evidence that taxol's actions on nicotinic receptor function may involve microtubules.