Lipoprotein-associated alpha-tocopheryl-succinate inhibits cell growth andinduces apoptosis in human MCF-7 and HBL-100 breast cancer cells

alpha-Tocopheryl succinate (alpha-TS) is a potent inhibitor of tumor cell p roliferation. The goal of the present study was to investigate whether and to what extent alpha-TS associates with plasma lipoproteins and if alpha-TS -enriched lipoproteins inhibit breast cancer cell growth in a manner compar able to the free drug. In vitro enrichment of human plasma revealed that al pha-TS readily associated with the main lipoprotein classes, findings confi rmed in vivo in mice. At the highest alpha-TS concentrations, lipoproteins carrying 50 000 (VLDL), 5000 (LDL) and 700 (HDL) alpha-TS molecules per lip oprotein particle were generated. alpha-TS enrichment generated lipoprotein particles with slightly decreased density and increased particle radius. T o study whether the level of LDL-receptor (LDL-R) expression affects alpha- TS uptake from apoB/E containing lipoprotein particles human breast cancer cells with low (MCF-7) and normal (HBL-100) LDL-R expression were used. The uptake of free, VLDL- and (apoE-free) HDL3-associated alpha-TS was nearly identical for both cell lines. In contrast, uptake of LDL-associated alpha- TS by HBL-100 cells (normar LDL-R expression) was about twice as high as co mpared to MCF-7 cells (low LDL-R expression). VLDL and LDL-associated alpha -TS inhibited proliferation most effectively at the highest concentration o f alpha-TS used (100% inhibition of MCF-7 growth with 20 mu g/ml of lipopro tein-associated alpha-TS). However, also a-TS-free VLDL and LDL inhibited H BL-100 cell proliferation up to 55%. In both cell lines, alpha-TS-enriched HDL3 inhibited cell growth by 40-60%. Incubation of both cell lines in the presence of free or lipoprotein-associated alpha-TS resulted in DNA fragmen tation indicative of apoptosis. Collectively, the present findings demonstr ate that: (1) alpha-TS readily associates with lipoproteins in vitro and in vivo; (2) the lipoprotein-enrichment efficacy was dependent on the particl e size and/or the triglyceride content of the lipoprotein; (3) uptake of LD L-associated alpha-TS was apparently dependent on the level of LDL-R expres sion; and (4) lipoproteins were efficient alpha-TS carriers inducing reduce d cell proliferation rates and apoptosis in human breast cancer cells as ob served for the free drug. (C) 2000 Elsevier Science B.V. All rights reserve d.