This is an essential consideration since all evidence that the taccalonolides don’t directly bind to and polymerize tubulin is based on biochemical reports that preclude cellular metabolism. The taccalonolides have IC50 values in these same cell lines which are 100-500 fold higher-than paclitaxel. Nevertheless, changes in interphase microtubules are evident at antiproliferative concentrations of taccalonolide A, increasing the likelihood c-Met kinase inhibitor that these changes could be involved in the system of taccalonolide induced cell death in vitro. This finding is of fascination with light of accumulating evidence that microtubule focused agents might be effective anti-cancer agents in the clinic because of their power to disrupt the varied functions of interphase and mitotic microtubules as opposed to only their antimitotic effects. 14 It is interesting to speculate that one of the reasons why taccalonolide An is indeed much more effective in vivo than would be expected from cellular studies is that its effects on interphase microtubules play an important part in its in vivo antitumor activity. The large difference between your concentrations of paclitaxel and taccalonolide A that cause interphase microtubule improvements and antiproliferative effects supports the hypothesis that those two drugs have similar, but mechanistically ribotide unique mechanisms of action. The differential potencies of taccalonolide An and paclitaxel have now been observed in a wide selection of biochemical, mobile and in vivo studies. In spite of the proven fact that taccalonolide A causes microtubule bundling in interphase cells at concentrations only 5 fold higher than paclitaxel, this propensity to cause cellular microtubule bundling doesn’t extend to biochemical studies where taccalonolide An is unable to improve microtubule polymerization even yet in the presence of a complete complement of cytosolic proteins. Additionally, previous reports are finding that taccalonolide An is 2 fold more potent than paclitaxel in a murine model. 12 These PF299804 data plainly demonstrate that the relationship between these two drugs is more difficult than will be predicted if taccalonolide A was simply binding to the taxane binding site with a different affinity than paclitaxel and further supports the theory that taccalonolide A has a unique mechanism of action as in comparison to other microtubule stabilizers. One explanation for the ability of taccalonolide A to cause microtubule stabilization in intact cells but not in biochemical preparations is that the drug is metabolized in cells to a molecule that binds to tubulin and initiates microtubule stabilization. If this metabolic rate also does occur systemically when taccalonolide An is used in vivo in murine models, then this could also reveal why taccalonolide An is indeed far more powerful in these models than would be expected from its IC50 in vitro.