title: Edelfosine lipid nanoparticles overcome multidrug resistance in K-562 leukemia cells by a caspase-independent mechanism.
abstract: The antitumor ether lipid edelfosine is the prototype of a novel generation of promising anticancer drugs that has been shown to be an effective antitumor agent in numerous malignancies. However, several cancer types display resistance to different antitumoral compounds due to multidrug resistance (MDR). Thus, MDR is a major drawback in anticancer therapy. In that sense, the leukemic cell line K-562 shows resistance to edelfosine. This resistance is overcome by the use of nanotechnology. The present work describes the rate and mechanism of internalization of free and nanoencapsulated edelfosine. The molecular mechanisms underlying cell death are described in the present paper by characterization of several molecules implied in the apoptosic and autophagic pathways (PARP, LC3IIB, caspases-3, -9 and -7), and their pattern of expression is compared with the cell induction in a sensitive cell line HL-60. Results showed different internalization patterns in both cells. Clathrin and lipid raft mediated endocytosis were observable in edelfosine uptake, whereas these mechanism were not visible in the uptake of lipid nanoparticles, which might suffer phagocytosis and macropinocytosis. Both treatments induced caspase-mediated apoptosis in HL-60 cells, whereas this cell death mechanism was unnoticeable in K-562 cells. Moreover, an important increase in autophagic vesicles was visible in K-562 cells. Thus, this mechanism might be implicated in overcoming K-562 resistance with the treatment by lipid nanoparticles.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra , C/Irunlarrea 1, E-31080 Pamplona, Spain.
authors.forename: María Ángela
authors.initials: MÁ
authors.lastname: Aznar
authors.forename: Beatriz
authors.initials: B
authors.lastname: Lasa-Saracíbar
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Blanco-Prieto
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D001343:Autophagy; D002851:Chromatography, High Pressure Liquid; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004705:Endocytosis; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D008055:Lipids / Q000737:chemistry*; D050997:Nanomedicine / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry*; D010742:Phospholipid Ethers / Q000008:administration & dosage*; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D008055:Lipids; D010742:Phospholipid Ethers; C026659:edelfosine