PM060184 belongs to a new family of tubulin-binding agents originally isolated from the marine sponge Lithoplocamia lithistoides. This compound is currently produced by total chemical synthesis and is under evaluation in Phase I clinical studies in patients with advanced cancer diseases. Recently published results indicate that members of the PM060184 family are interfacial microtubule inhibitors that bind with nanomolar affinity to unassembled αβ-tubulin dimers at the beta tubulin plus end (Pera et al. 2013, ACS Chem. Biol.) In an attempt to shed light into the mechanism responsible of its antitumor activity, we have studied the effects of PM060184 in tumor cells including microtubule network structure, centrosome modifications and type of cell death induced by this compound. PM060184 rapidly internalizes into the tumor cells and shows a high intracellular retention rate, reflecting the high avidity for its cellular target. In addition, the antitumor activity of the compound seems to be rather irreversible after short (30 min) exposure times. At the cellular level, PM060184 inhibits tubulin polymerization. Interestingly, PM060184 affects interphase cells, where the compound induces disorganisation and fragmentation of the microtubule network and disturbing cell migration. PM060184 also affects mitotic cells, inducing the appearance of multipolar mitosis and lagging chromosomes at the metaphase plate. All these effects correlate with prometaphase arrest and induction of caspase-dependent apoptosis or appearance of cells in a multinucleated interphase-like state unrelated to classical apoptosis pathways. In summary, these results indicate that PM060184 represents a new tubulin binding agent with promising potential as an anticancer agent.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A177.

Citation Format: Marta Martínez-Diez, Juan Fernando Martínez-Leal, Luis F. Garcia-Fernandez, Carlos M. Galmarini. Mode of action of PM060184, a new interfacial microtubule inhibitor of marine origin. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A177.