Antiangiogenic and antitumoral activity of phenyl-3-(2-chloroethyl)ureas: a class of soft alkylating agents disrupting microtubules that are unaffected by cell adhesion-mediated drug resistance

Cancer Research
Eric PetitclercRené C -Gaudreault

Abstract

The development of new anticancer agents with lower toxicity, higher therapeutic index, and weaker tendency to induce resistant phenotypes in tumor cells is a continuous challenge for the scientific community. Toward that end, we showed previously that a new class of soft alkylating agents designed as phenyl-3-(2-chloroethyl)ureas (CEUs) inhibits tumor cell growth in vitro and that their efficiency is not altered by clinically relevant mechanisms of resistance such as overexpression of multidrug resistance proteins, increase in intracellular concentration of glutathione and/or glutathione S-transferase activity, alteration of topoisomerase II, and increased DNA repair. Mechanistic studies have showed recently that the cytotoxic activity of several CEUs was mainly related to the disruption of microtubules. Here, we present results supporting our assumption that 4-tert-butyl-[3-(2-chloroethyl)ureido]phenyl (tBCEU) (and its bioisosteric derivative 4-iodo-[3-(2-chloroethyl)ureido]phenyl (ICEU) are potent antimicrotubule agents both in vitro and in vivo. They covalently bind to beta-tubulin, leading to a microtubule depolymerization phenotype, consequently disrupting the actin cytoskeleton and altering the nuclear morphology. Accord...Continue Reading

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Citations

Apr 3, 2013·Molecular and Cellular Biology·Marie-Josée FournierRachid Mazroui
Aug 21, 2014·Angiogenesis·Patrycja Nowak-SliwinskaM Luisa Iruela-Arispe
Nov 16, 2010·Canadian Journal of Physiology and Pharmacology·Alexandre PatenaudeEric Petitclerc
Oct 25, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Łukasz BalewskiAnna Makowska
May 27, 2008·Bioorganic & Medicinal Chemistry Letters·Jessica S FortinRené C-Gaudreault
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