RESUMEN
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 beta-tubulin and on alpha-tubulin and beta-tubulin (A549.EpoB40/A549.EpoB480 resistant to epothilone B or paclitaxel). IRC-083927 displayed cell cycle arrest in G(2)-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.
Asunto(s)
Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Imidazoles/farmacología , Sulfonamidas/farmacología , Tubulina (Proteína)/metabolismo , Animales , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Ciclo Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Humanos , Ratones , Neovascularización Patológica , Trasplante HeterólogoRESUMEN
A series of 22-hydroxyacuminatine analogs was prepared by using different Friedländer condensations. Several of the new compounds were tested for antiproliferative activity on cancer cell lines and for topoisomerase I inhibitory activity.
Asunto(s)
Antineoplásicos/farmacología , Indolizinas/síntesis química , Neoplasias/tratamiento farmacológico , Quinolinas/síntesis química , Antineoplásicos/síntesis química , ADN-Topoisomerasas de Tipo I/genética , Humanos , Indolizinas/química , Indolizinas/farmacología , Estructura Molecular , Neoplasias/enzimología , Quinolinas/química , Quinolinas/farmacología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I , Células Tumorales CultivadasRESUMEN
BN80927 belongs to a novel family of camptothecin analogs, the homocamptothecins, developed on the concept of topoisomerase I (Topo I) inhibition and characterized by a stable seven-membered beta-hydroxylactone ring. Preclinical data reported here show that BN80927 retains Topo I poisoning activity in cell-free assay (DNA relaxation) as well as in living cells, in which in vivo complexes of topoisomerase experiments and quantification of DNA-protein-complexes stabilization, have confirmed the higher potency of BN80927 as compared with the Topo I inhibitor SN38. In addition, BN80927 inhibits Topo II-mediated DNA relaxation in vitro but without cleavable-complex stabilization, thus indicating catalytic inhibition. Moreover, a Topo I-altered cell line (KBSTP2), resistant to SN38, remains sensitive to BN80927, suggesting that a part of the antiproliferative effects of BN80927 are mediated by a Topo I-independent pathway. This hypothesis is also supported by in vitro data showing an antiproliferative activity of BN80927 on a model of resistance related to the noncycling state of cells (G(0)-G(1) synchronized). In cell growth assays, BN80927 is a very potent antiproliferative agent as shown by IC(50) values consistently lower than those of SN38 in tumor cell lines as well as in their related drug-resistant lines. BN80927 shows high efficiency in vivo in tumor xenograft studies using human androgen-independent prostate tumors PC3 and DU145. Altogether, these data strongly support the clinical development of BN80927.
Asunto(s)
Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Camptotecina/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/sangre , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Animales , Camptotecina/sangre , División Celular/efectos de los fármacos , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo I/metabolismo , ADN-Topoisomerasas de Tipo II/metabolismo , ADN Superhelicoidal/efectos de los fármacos , ADN Superhelicoidal/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Inhibidores Enzimáticos/farmacología , Células HL-60 , Humanos , Células K562 , Masculino , Ratones , Ratones Desnudos , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Hormono-Dependientes/patología , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , Inhibidores de Topoisomerasa I , Inhibidores de Topoisomerasa II , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Vinblastine and vinorelbine analogues have been synthesised by reacting new versatile electrophilic vindoline derivatives with various 3-substituted indoles. The resulting compounds have been evaluated for their antimitotic properties, but exhibited less potent activities in comparison with the standard binary Vinca alkaloids.