title: The seco-taxane IDN5390 is able to target class III beta-tubulin and to overcome paclitaxel resistance.
abstract: A prominent mechanism of drug resistance to taxanes is the overexpression of class III beta-tubulin. The seco-taxane IDN5390 was chosen for its selective activity in paclitaxel-resistant cells with an overexpression of class III beta-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 beta-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 beta-tubulin levels. Such properties can be explained by taking into consideration the composition of class III beta-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 alpha-unsaturated enol-keton moiety better fits with class III beta-tubulin than paclitaxel at the binding site. Taking altogether, these findings indicate that the concomitant treatment IDN5390/paclitaxel is able to successfully target class I and III beta-tubulin and the combined use of two taxanes with diverse spectrum activity against tubulin isotypes could represent a novel approach to overcome paclitaxel resistance.
authors.affiliation: Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy. cferlini@rm.unicatt.it
authors.forename: Cristiano
authors.initials: C
authors.lastname: Ferlini
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Raspaglio
authors.forename: Simona
authors.initials: S
authors.lastname: Mozzetti
authors.forename: Lucia
authors.initials: L
authors.lastname: Cicchillitti
authors.forename: Flavia
authors.initials: F
authors.lastname: Filippetti
authors.forename: Daniela
authors.initials: D
authors.lastname: Gallo
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008958:Models, Molecular; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001952:Bridged-Ring Compounds; C459840:IDN 5390; D043823:Taxoids; D014404:Tubulin; D017239:Paclitaxel