Disruption of cellular cholesterol transport and homeostasis as a novel mechanism of action of membrane-targeted alkylphospholipid analogues.

摘要: Background and purpose: Alkylphospholipid (APL) analogues constitute a new class of synthetic anti-tumour agents that act directly on cell membranes. We have previously demonstrated hexadecylphosphocholine (HePC) alters intracellular cholesterol traffic metabolism in HepG2 cells. now extended our studies to analyse the effects other clinically relevant APLs, such as edelfosine, erucylphosphocholine perifosine homeostasis. Experimental approach: Using radiolabelled substrates we determined effect APLs from plasma membrane endoplasmic reticulum (ER). Protein levels gene expression main proteins involved homeostasis were analysed by Western blot RT-PCR respectively. Membrane raft non-raft fractions isolated cells detergent-free method. Key results: All inhibited transport ER, which induced significant cholesterogenic response This an increased higher several related biosynthesis receptor-mediated uptake cholesterol. Cell exposure APL-representative HePC enhanced content mainly fractions, compared with untreated Conclusions implications: Membrane-targeted exhibited novel common mechanism action, through disruption homeostasis, turn affected specific lipid microdomains cellular British Journal Pharmacology (2010) 160, 355‐366; doi:10.1111/j.1476-5381.2010.00689.x