Edelfosine lipid nanoparticles overcome MDR in K-562 leukemia cells by caspaseindependent mechanism

Abstract

The anti-tumor ether lipid edelfosine is the prototype of a novel generation of promising anticancer drugs that has been shown to be an effective anti-tumor agent in numerous malignancies. However, several cancer types display resistance to different anti-tumor compounds due to multi-drug resistance (MDR), which is a major drawback in anticancer therapy. The leukemic cell line K-562 shows resistance to edelfosine, which can be overcome by the use of nanotechnology. The present paper describes the rate and mechanism of internalization of free and nano-encapsulated edelfosine. The molecular mechanisms underlying this cell death is described in the present paper by characterization of several molecules implied in the apoptotic and autophagic pathways (PARP, LC3IIB, Caspases-3, - 9 and -7) and the pattern of expression is compared with cell induction in a sensitive cell line HL-60. The results showed different internalization patterns in both cells. Clathrin and lipid raftmediated 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 endorsed caspase-mediated apoptosis in HL-60 cells but this cell death was not observed in K-562 cells. Moreover, an important increase in autophagic vesicles was visible in K-562 cells. Thus, this mechanism might be implicated in the overcoming of K-562 resistance to the treatment by lipid nanoparticles.