title: Enhanced docetaxel-mediated cytotoxicity in human prostate cancer cells through knockdown of cofilin-1 by carbon nanohorn delivered siRNA.
abstract: We synthesized a non-viral delivery system (f-CNH3) for small interfering RNA (siRNA) by anchoring a fourth-generation polyamidoamine dendrimer (G4-PAMAM) to carbon nanohorns (CNHs). Using this new compound, we delivered a specific siRNA designed to knockdown cofilin-1, a key protein in the regulation of cellular cytoskeleton, to human prostate cancer (PCa) cells. The carbon nanohorn (CNH) derivative was able to bind siRNA and release it in the presence of an excess of the polyanion heparin. Moreover, this hybrid nanomaterial protected the siRNA from RNAse-mediated degradation. Synthetic siRNA delivered to PCa cells by f-CNH3 decreased the cofilin-1 mRNA and protein levels to about 20% of control values. Docetaxel, the drug of choice for the treatment of PCa, produced a concentration-dependent activation of caspase-3, an increase in cell death assessed by lactate dehydrogenase release to the culture medium, cell cycle arrest and inhibition of tumor cell proliferation. All of these toxic effects were potentiated when cofilin-1 was down regulated in these cells by a siRNA delivered by the nanoparticle. This suggests that knocking down certain proteins involved in cancer cell survival and/or proliferation may potentiate the cytotoxic actions of anticancer drugs and it might be a new therapeutic approach to treat tumors.
authors.affiliation: NanoDrugs, S.L. Parque Científico y Tecnológico, 02071 Albacete, Spain.
authors.forename: Francisco C
authors.initials: FC
authors.lastname: Pérez-Martínez
authors.forename: Blanca
authors.initials: B
authors.lastname: Carrión
authors.forename: Maria I
authors.initials: MI
authors.lastname: Lucío
authors.forename: Noelia
authors.initials: N
authors.lastname: Rubio
authors.forename: María A
authors.initials: MA
authors.lastname: Herrero
authors.forename: Ester
authors.initials: E
authors.lastname: Vázquez
authors.forename: Valentín
authors.initials: V
authors.lastname: Ceña
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002244:Carbon / Q000737:chemistry; D045744:Cell Line, Tumor; D051338:Cofilin 1 / Q000235:genetics*; D050091:Dendrimers / Q000737:chemistry; D000077143:Docetaxel; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D049329:Nanostructures / Q000737:chemistry; D009757:Nylons / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D043823:Taxoids / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D051338:Cofilin 1; D050091:Dendrimers; D009757:Nylons; C520550:PAMAM-G4; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; D002244:Carbon