Tocotrienol-induced cytotoxicity is unrelated to mitochondrial stress apoptotic signaling in neoplastic mammary epithelial cells.
Tocotrienols and tocopherols represent the 2 subgroups within the vitamin E family of compounds, but tocotrienols display significantly greater apoptotic activity against a variety of cancer cell types. However, the exact mechanism mediating tocotrienol-induced apoptosis is not understood. Studies were conducted to determine the effects of tocotrienols on mitochondrial-stress-mediated apoptotic signaling in neoplastic +SA mammary epithelial cells grown in vitro. Exposure for 24 h to 0-20 micromol/L gamma-tocotrienol resulted in a dose-responsive increase in +SA cells undergoing apoptosis, as determined by flow cytometric analysis of Annexin V staining. However, tocotrienol-induced apoptosis was not associated with a disruption or loss of mitochondrial membrane potential, or the release of mitochondrial cytochrome c into the cytoplasm, as determined by JC-1 flow cytometric staining and ELISA assay, respectively. Interestingly, apoptotic +SA cells showed a paradoxical decrease in mitochondrial levels of pro-apoptotic proteins Bid, Bax, and Bad, and a corresponding increase in mitochondrial levels of anti-apoptotic proteins, Bcl-2 and Bcl-xL, suggesting that mitochondrial membrane stability and integrity might actually be enhanced for a limited period of time following acute tocotrienol exposure. In summary, these findings clearly demonstrate that tocotrienol-induced apoptosis occurs independently of mitochondrial stress apoptotic signaling in neoplastic +SA mammary epithelial cells.
Shah
Sumit J
SJ
School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0470, USA.
Sylvester
Paul W
PW
D000818:Animals; D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival; D002839:Chromans / Q000494:pharmacology / Q000633:toxicity*; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D019254:Genes, bcl-2 / Q000235:genetics; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D013314:Stress, Mechanical; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity
D017304:Annexin A5; D002839:Chromans; D014810:Vitamin E; C013649:plastochromanol 8; D045304:Cytochromes c