title: Administration of the optimized β-Lapachone-poloxamer-cyclodextrin ternary system induces apoptosis, DNA damage and reduces tumor growth in a human breast adenocarcinoma xenograft mouse model.
abstract: β-Lapachone (β-Lap) is a 1,2-orthonaphthoquinone that selectively induces cell death in human cancer cells through NAD(P)H:quinone oxidoreductase-1 (NQO1). NQO1 is overexpressed in a variety of tumors, as compared to normal adjacent tissue. However, the low solubility and non-specific distribution of β-Lap limit its suitability for clinical assays. We formulated β-Lap in an optimal random methylated-β-cyclodextrin/poloxamer 407 mixture (i.e., β-Lap ternary system) and, using human breast adenocarcinoma MCF-7 cells and immunodeficient mice, performed in vitro and in vivo evaluation of its anti-tumor effects on proliferation, cell cycle, apoptosis, DNA damage, and tumor growth. This ternary system is fluid at room temperature, gels over 29 °C, and provides a significant amount of drug, thus facilitating intratumoral delivery, in situ gelation, and the formation of a depot for time-release. Administration of β-Lap ternary system to MCF-7 cells induces an increase in apoptosis and DNA damage, while producing no changes in cell cycle. Moreover, in a mouse xenograft tumor model, intratumoral injection of the system significantly reduces tumor volume, while increasing apoptosis and DNA damage without visible toxicity to liver or kidney. These anti-tumoral effects and lack of visible toxicity make this system a promising new therapeutic agent for breast cancer treatment.
authors: Departamento de Fisiología-Centro de Investigacion en Medicina Molecular e Enfermidades Crónicas, Universidad de Santiago de Compostela, Spain.
authors: Samuel
authors: S
authors: Seoane
authors: Patricia
authors: P
authors: Díaz-Rodríguez
authors: Juan
authors: J
authors: Sendon-Lago
authors: Rosalia
authors: R
authors: Gallego
authors: Román
authors: R
authors: Pérez-Fernández
authors: Mariana
authors: M
authors: Landin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003505:Cyclodextrins / Q000008:administration & dosage*; D004249:DNA Damage / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009285:Naphthoquinones / Q000008:administration & dosage*; D020442:Poloxamer / Q000008:administration & dosage*; D012212:Rheology; D013696:Temperature; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003505:Cyclodextrins; D009285:Naphthoquinones; D020442:Poloxamer; C014638:beta-lapachone