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Liberatore, Anne-Marie; Coulomb, Hélène; Pons, Dominique; Dutruel, Olivier; Kasprzyk, Philip G.; Carlson, Mark; Nelson, Ann Savola; Newman, Simon P.; Stengel, Chloe; Auvray, Pierrïck; Hesry, Vincent; Foll, Béatrice; Narboux, Nadine; Morlais, Delphine; Le Moing, Mélissa; Bernetiere, Sonia; Dellile, Raphael; Camara, Jose; Ferrandis, Eric; Bigg, Dennis C.; Prévost, Grégoire P.

IRC-083927 is a new tubulin binder that inhibits growth of human tumor cells resistant to standard tubulin-binding agents

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  • Media type: E-Article
  • Title: IRC-083927 is a new tubulin binder that inhibits growth of human tumor cells resistant to standard tubulin-binding agents
  • Contributor: Liberatore, Anne-Marie; Coulomb, Hélène; Pons, Dominique; Dutruel, Olivier; Kasprzyk, Philip G.; Carlson, Mark; Nelson, Ann Savola; Newman, Simon P.; Stengel, Chloe; Auvray, Pierrïck; Hesry, Vincent; Foll, Béatrice; Narboux, Nadine; Morlais, Delphine; Le Moing, Mélissa; Bernetiere, Sonia; Dellile, Raphael; Camara, Jose; Ferrandis, Eric; Bigg, Dennis C.; Prévost, Grégoire P.
  • Published: American Association for Cancer Research (AACR), 2008
  • Published in: Molecular Cancer Therapeutics, 7 (2008) 8, Seite 2426-2434
  • Language: English
  • DOI: 10.1158/1535-7163.mct-08-0208
  • ISSN: 1535-7163; 1538-8514
  • Origination:
  • Footnote:
  • Description: Abstract Tubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubule-interacting agents is limited by the fact that they are substrates for drug efflux pumps (P-glycoprotein) and/or by the acquisition of point mutations in tubulin residues important for drug-tubulin binding. To bypass these resistance systems, we have identified and characterized a novel synthetic imidazole derivative IRC-083927, which inhibits the tubulin polymerization by a binding to the colchicine site. IRC-083927 inhibits in vitro cell growth of human cancer cell lines in the low nanomolar range. More interesting, it remains highly active against cell lines resistant to microtubule-interacting agents (taxanes, Vinca alkaloids, or epothilones). Such resistances are due to the presence of efflux pumps (NCI-H69/LX4 resistant to navelbine and paclitaxel) and/or the presence of mutations on β-tubulin and on α-tubulin and β-tubulin (A549.EpoB40/A549.EpoB480 resistant to epothilone B or paclitaxel). IRC-083927 displayed cell cycle arrest in G2-M phase in tumor cells, including in the drug-resistant cells. In addition, IRC-083927 inhibited endothelial cell proliferation in vitro and vessel formation in the low nanomolar range supporting an antiangiogenic behavior. Finally, chronic oral treatment with IRC-083927 (5 mg/kg) inhibits the growth of two human tumor xenografts in nude mice (C33-A, human cervical cancer and MDA-MB-231, human hormone-independent breast cancer). Together, the antitumor effects induced by IRC-083927 on tumor models resistant to tubulin agents support further investigations to fully evaluate its potential for the treatment of advanced cancers, particularly those resistant to current clinically available drugs. [Mol Cancer Ther 2008;7(8):2426–34]
  • Access State: Open Access