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

2000; Elsevier BV; Volume: 1485; Issue: 2-3 Linguagem: Inglês

10.1016/s1388-1981(00)00035-4

1879-2618

Pirkko J. Pussinen, Helmut Lindner, Otto Glatter, Helga Reicher, Gerhard M. Kostner, Andrea Wintersperger, Ernst Malle, Wolfgang Sattler,

Estrogen and related hormone effects

α-Tocopheryl succinate (α-TS) is a potent inhibitor of tumor cell proliferation. The goal of the present study was to investigate whether and to what extent α-TS associates with plasma lipoproteins and if α-TS-enriched lipoproteins inhibit breast cancer cell growth in a manner comparable to the free drug. In vitro enrichment of human plasma revealed that α-TS readily associated with the main lipoprotein classes, findings confirmed in vivo in mice. At the highest α-TS concentrations, lipoproteins carrying 50 000 (VLDL), 5000 (LDL) and 700 (HDL) α-TS molecules per lipoprotein particle were generated. α-TS enrichment generated lipoprotein particles with slightly decreased density and increased particle radius. To study whether the level of LDL-receptor (LDL-R) expression affects α-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 α-TS was nearly identical for both cell lines. In contrast, uptake of LDL-associated α-TS by HBL-100 cells (normal LDL-R expression) was about twice as high as compared to MCF-7 cells (low LDL-R expression). VLDL and LDL-associated α-TS inhibited proliferation most effectively at the highest concentration of α-TS used (100% inhibition of MCF-7 growth with 20 μg/ml of lipoprotein-associated α-TS). However, also α-TS-free VLDL and LDL inhibited HBL-100 cell proliferation up to 55%. In both cell lines, α-TS-enriched HDL3 inhibited cell growth by 40–60%. Incubation of both cell lines in the presence of free or lipoprotein-associated α-TS resulted in DNA fragmentation indicative of apoptosis. Collectively, the present findings demonstrate that: (1) α-TS readily associates with lipoproteins in vitro and in vivo; (2) the lipoprotein-enrichment efficacy was dependent on the particle size and/or the triglyceride content of the lipoprotein; (3) uptake of LDL-associated α-TS was apparently dependent on the level of LDL-R expression; and (4) lipoproteins were efficient α-TS carriers inducing reduced cell proliferation rates and apoptosis in human breast cancer cells as observed for the free drug.