The seco-taxane IDN5390 is able to target class III beta-tubulin and to overcome paclitaxel resistance

A prominent mechanism of drug resistance to taxanes is the overexpression of class III β-tabulin. The seco-taxane IDN5390 was chosen for its selective activity in paclitaxel-resistant cells with an overexpression of class III β-tubulin. Moreover, the combined treatment paclitaxel/IDN5390 yielded a strong synergism, which was also evident in cell-free tubulin polymerization assays. In the presence of an anti-class III β-tubulin as a blocking antibody, tubulin polymerization induced by paclitaxel and IDN5390 was enhanced and not affected, respectively, whereas synergism was abolished, thereby indicating that IDN5390 activity is not modulated by class III β-tabulin levels. Such properties can be explained by talcing into consideration the composition of class III β-tubulin paclitaxel binding site; in fact, Ser277 interacting with paclitaxel C group in class I is replaced by an Arginine in class III. IDN5390 that has an open and flexible C ring and an acidic α-unsatarated enol-keton moiety better fits with class III β-tubulin than paclitaxel at the binding site. Taken altogether, these findings indicate that the concomitant treatment IDN5390/paclitaxel is able to successfully target class I and III β-tubulin and the combined use of two taxanes with diverse spectrum activity against tubulin isotypes could represent a novel approach to overcome paclitaxel resistance. ©2005 American Association for Cancer Research.