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.
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. Accordingly, tBCEU and ICEU also inhibited the migration and proliferation of endothelial and tumor cells in vitro in a dose-dependent manner. It is noteworthy that ICEU efficiently blocked angiogenesis and tumor growth in three distinct animal models: (a) the Matrigel plug angiogenesis assay; (b) the CT-26 tumor growth assay in mice; and (c) the chick chorioallantoic membrane tumor assay. In addition, we present evidence that CEU cytotoxicity is unaffected by additional resistance mechanisms impeding tumor response to DNA alkylating agents such as cisplatin, namely the cell adhesion mediated-drug resistance mechanism, which failed to influence the cytocidal activity of CEUs. On the basis of the apparent innocuousness of CEUs, on their ability to circumvent many classical and recently described tumor cell resistance mechanisms, and on their specific biodistribution to organs of the gastrointestinal tract, our results suggest that CEUs represent a promising new class of anticancer agents.
Petitclerc
Eric
E
Centre de Recherche, Unité de Biotechnologie et de Bioingénierie, CHUQ, Hôpital Saint-François d'Assise, Québec, Canada.
Deschesnes
Réna G
RG
Côté
Marie-France
MF
Marquis
Claude
C
Janvier
Richard
R
Lacroix
Jacques
J
Miot-Noirault
Elisabeth
E
Legault
Jean
J
Mounetou
Emmanuelle
E
Madelmont
Jean-Claude
JC
C -Gaudreault
René
R
D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002642:Chick Embryo; D003078:Colchicine / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D006224:Cricetinae; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D000199:Actins; D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D014404:Tubulin; D014508:Urea; D017239:Paclitaxel; D003078:Colchicine