Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/61564
Title: Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures
Author: Furlan, Alessandro
Roux, Benjamin
Lamballe, Fabienne
Conti, Filippo
Issaly, Nathalie
Daian, Fabrice
Guillemot, Jean-François
Richelme, Sylvie
Contensin, Magali
Bosch Cartes, Joan
Passarella, Daniele
Piccolo, Oreste
Dono, Rosanna
Maina, Flavio
Keywords: Càncer
Cèl·lules canceroses
Medicaments antineoplàstics
Dianes farmacològiques
Desenvolupament de medicaments
Tiazoles
Expressió gènica
Cancer
Cancer cells
Antineoplastic agents
Drug targeting
Drug development
Thiazoles
Gene expression
Issue Date: 5-Oct-2012
Publisher: Public Library of Science (PLoS)
Abstract: The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by 'RTK swapping' by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation.
Note: Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.pone.0046738
It is part of: PLoS One, 2012, vol. 7, num. 10, p. e46738
Related resource: http://dx.doi.org/10.1371/journal.pone.0046738
URI: http://hdl.handle.net/2445/61564
ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

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