Inhibition of lung carcinoma cell growth by high density lipoprotein-associated alpha-tocopheryl-succinate.
Alpha-tocopheryl-succinate (alphaTS) is a synthetic, anti-neoplastic derivative of alpha-tocopherol. Here we studied the effects of free and high-density lipoprotein subclass 3 (HDL3)-associated alphaTS on the growth of human (A549) and mouse Lewis (LL2) lung carcinoma cells. Both free and HDL3-associated alphaTS inhibited A549 growth in a time- and concentration-dependent manner. Treatment of A549 cells with alphaTS-enriched HDL3 led to DNA fragmentation and a time-dependent decrease in immunoreactivity of poly(ADP-ribose)polymerase. Uptake experiments revealed a high capacity for selective alphaTS uptake in excess of holoparticle endocytosis. Overexpression of scavenger receptor class B, type I (SR-BI), the prime receptor mediating selective lipid uptake, in A549 cells resulted in significantly increased selective alphaTS uptake, a finding associated with complete cellular growth arrest. The present in vitro findings were verified in an in vivo model: tumor inoculation in C57BL6 was performed with either wild-type, beta-galactosidase- or SR-BI-overexpressing LL2 cells. After tumor inoculation, the animals received six consecutive intravenous injections of alphaTS. This experimental setup resulted in significantly reduced tumor burden in animals that were inoculated with SR-BI-overexpressing LL2 cells but not in animals inoculated with wild-type or beta-galactocidase-transfected cells. Based on our in vitro and in vivo findings, we propose that SR-BI could provide a novel route for HDL3-mediated drug delivery of anti-neoplastic drugs.
Hrzenjak
A
A
Institute of Pathology, Medical University Graz, Harrachgasse 21, 8010 Graz, Austria.
Reicher
H
H
Wintersperger
A
A
Steinecker-Frohnwieser
B
B
Sedlmayr
P
P
Schmidt
H
H
Nakamura
T
T
Malle
E
E
Sattler
W
W
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018955:CD36 Antigens; D002277:Carcinoma / Q000188:drug therapy*; D002455:Cell Division; D045744:Cell Line, Tumor; D002499:Centrifugation, Density Gradient; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D006801:Humans; D006868:Hydrolysis; D007150:Immunohistochemistry; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009707:Nucleosomes / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D013997:Time Factors; D024505:Tocopherols; D014162:Transfection; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000378:metabolism
D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D009707:Nucleosomes; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D014810:Vitamin E; D011065:Poly(ADP-ribose) Polymerases; D001616:beta-Galactosidase; D024505:Tocopherols