Gamma- and delta-tocotrienols exert a more potent anticancer effect than alpha-tocopheryl succinate on breast cancer cell lines irrespective of HER-2/neu expression.
OBJECTIVE
Breast cancer is the most common malignancy among women, with an age-specific incidence profile. During the last years much evidence has accumulated demonstrating the anticancer activity of tocotrienols (T3), a subfamily of natural vitamin E (VE). In this study, mouse and human breast cancer cells (with or without HER-2/neu oncogene overexpression) were used to investigate the anticancer effect of alpha-, gamma-, and delta-tocotrienols in comparison with alpha-tocopheryl succinate (alpha-TOS), a synthetic derivative with widely recognized anticancer properties.


METHODS
Human and mouse breast cancer cell lines were used. The effect of VE compounds on cell viability was investigated using Alamar Blue assay. Apoptosis was assessed by propidium iodide and JC-1 staining. Expression of senescence-associated markers was evaluated by RT-PCR and Western blot analysis was used to examine the changes in the expression levels of HER-2/neu.


RESULTS
gamma- and delta-Tau3 reduced cell viability with IC(50) values of less than half those of alpha-T3 and alpha-TOS. gamma- and delta-Tau3, and alpha-TOS to a lesser extent, induced apoptosis possibly via the mitochondrial pathway, and the expression of senescent-like growth arrest markers as p53, p21, and p16. Both alpha-TOS and tocotrienols downregulated HER-2/neu in tumor cells overexpressing this oncogene, but this effect did not seem to be essential for the antitumor activity of these compounds.


CONCLUSIONS
We demonstrate that in HER-2/neu breast cancer cells, the non-alpha form of T3 shows stronger anticancer activity than the synthetic VE-derivative alpha-TOS and this effect occurs independently from the inhibition of HER-2/neu oncogene expression.
Pierpaoli
Elisa
E
Laboratory of Tumor Immunology, INRCA-IRCCS, Scientific Technological Area, Ancona, Italy.
Viola
Valentina
V
Pilolli
Francesca
F
Piroddi
Marta
M
Galli
Francesco
F
Provinciali
Mauro
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D024508:Tocotrienols; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002839:Chromans; D018719:Erb-b2 Receptor Tyrosine Kinases; D024508:Tocotrienols; D014810:Vitamin E; D024502:alpha-Tocopherol; C082097:tocotrienol, delta; C013649:plastochromanol 8; C082032:tocotrienol, alpha