Biological properties of jatrophane polyesters, new microtubule-interacting agents.
OBJECTIVE
The biological activities of macrocyclic jatrophane polyesters 1-3 from the Sardinian endemism Euphorbia semiperfoliata Viv. have not been evaluated in depth. We investigated the microtubule-interacting and antiproliferative activities of these drugs and the molecular mechanisms underlying their effects.


METHODS
We tested jatrophanes for their interaction with purified bovine brain tubulin by an in vitro polymerization assay and by electron microscopy. At a cellular level, the effects of jatrophanes on microtubular architecture, nuclear morphology, cell viability, cell cycle perturbations, and p53 and Raf-1/Bcl-2 involvement were investigated.


RESULTS
Jatrophanes exhibited microtubule-interacting activity. They stimulated purified tubulin assembly in vitro, and induced paclitaxel-like microtubules, as revealed by electron microscopy. In the cells, rearrangement of microtubule architecture was in contrast to the bundling produced by paclitaxel. Jatrophanes inhibited the growth of some human cancer cell lines without inducing cell cycle arrest in the G2/M phase. Moreover, they influenced p53 expression and Raf-1/Bcl-2 activation.


CONCLUSIONS
Despite their structural difference from paclitaxel and other microtubule-interacting agents, jatrophanes may represent a new type of tubulin binder.
Miglietta
Antonella
A
Department of Experimental Medicine and Oncology, Università di Torino, Corso Raffaello 30, 10125 Torino, Italy. antonella.miglietta@unito.it
Gabriel
Ludovica
L
Appendino
Giovanni
G
Bocca
Claudia
C
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D028481:Euphorbia / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology; D011091:Polyesters / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004224:Diterpenes; D011091:Polyesters; D014404:Tubulin; D017239:Paclitaxel