title: Mitochondria-specific pro-apoptotic activity of genistein lipidic nanocarriers.
abstract: Genistein (Gen) soy isoflavone produces extensive pro-apoptotic anticancer effects, mediated predominantly via induction of mitochondrial damages. Rationalization of the native mitochondrial selectivity of Gen, utilizing biophysical model assumptions, led to our design of cationic lipid-based nanocarriers (NC) of Gen. Prototype nanoformulations, lipidic micelles (Mic) and nanoemulsions (NEs) incorporated Gen to serve as both therapeutic and targeting moieties, specific for mitochondria. Both Gen-NCs, showing superior physicochemical properties, produced significant cytotoxicity (5-10-fold lower EC50), compared to all drug controls, in hepatic and colon carcinomas. Owing to the mitochondria-specific accumulation of Gen-NCs, their mitochondrial depolarization effect was most evident, leading to marked activation of intrinsic apoptotic pathway markers--cytosolic cytochrme c and specific caspase-9--thus, confirming the direct mitochondrial action of Gen-NCs. This mechanistic evidence of the mitochondria specificity of our Gen-NE and Gen-Mic strongly indicates their potential as targeted delivery nanosystems to augment anticancer efficacy of many lipophilic chemotherapeutics.
authors.affiliation: Arizona College of Osteopathic Medicine and §Department of Pharmaceutical Sciences, College of Pharmacy-Glendale, Midwestern University , 19555 North 59th Avenue, Glendale, Arizona 85308, United States.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Pham
authors.forename: Bill
authors.initials: B
authors.lastname: Brownlow
authors.forename: Tamer
authors.initials: T
authors.lastname: Elbayoumi
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D045304:Cytochromes c / Q000378:metabolism; D004655:Emulsions; D004797:Enzyme-Linked Immunosorbent Assay; D019833:Genistein / Q000008:administration & dosage / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007529:Isoflavones / Q000008:administration & dosage / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008823:Micelles; D008928:Mitochondria / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D004655:Emulsions; D007529:Isoflavones; D008823:Micelles; D045304:Cytochromes c; D019833:Genistein; D020169:Caspases