Effects of taxoids from Taxus cuspidata on microtubule depolymerization and vincristine accumulation in MDR cells

Among new taxoids, taxuspines A H and J T (1 19), and known taxoids 20 56 containing taxol (56) and taxol-type compounds 37 44 with an N-acylphenylisoserine group at C-13 and an oxetane ring at C-4 and C-5 isolated from stems and leaves of the Japanese yew Taxus cuspidata Sieb. et Zucc., non-taxol-type compounds 4 and 32 remarkably reduced CaCl2-induced depolemerization of microtubules. Furthermore, some non-taxol-type compounds 2, 3, 9, 24, 25, 27, and 28 increased cellular accumulation of vincristine in multidrug-resistant tumor cells as potent as verapamil, while taxol (36) and taxol-type compounds did not show such an activity. In addition, the non-taxol-type compounds enhancing vincristine accumulation inhibited competitively binding of azidopine to P-glycoprotein. These results suggest that some non-taxol-type taxoids may be useful for overcoming multidrug resistance in tumor cells.