Growth inhibitory action of brefeldin A with taxol and tiazofurin in human breast carcinoma cells.

Abstract

Brefeldin A (NSC 89671), a macrocyclic lactone, blocks cellular protein transport by disturbing the association and dissociation of the Golgi apparatus with a 110-kD protein which is regulated by GTP. Brefeldin also induces retrograde transport from the Golgi membrane to the endoplasmic reticulum, which is mediated by microtubules which also require GTP for their biosynthesis. The anti-cancer action of taxol is exerted by enhancing tubulin polymerization in microtubule assembly; tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 28693) acts through decreasing cellular GTP concentrations. Therefore, we tested the hypothesis that taxol (paclitaxel, NSC 125975) or tiazofurin might provide synergism with brefeldin. In human breast carcinoma MDA-MB-435 cells in the growth inhibition assays for brefeldin, taxol and tiazofurin, the IC50s were 41 nM, 6 nM and 13 microM, respectively. When brefeldin and taxol were given simultaneously, addition (brefeldin 10 nM with taxol 2 to 8 nM) or synergism (brefeldin 30 nM with taxol 2 to 8 nM) was observed. When brefeldin and tiazofurin were given simultaneously, or tiazofurin was followed 12 h later by brefeldin, addition was observed. The protocols yielding synergism and addition should be of value in the design of clinical trials for breast carcinoma.