In vivo and in vitro studies of anticancer actions of alpha-TEA for human prostate cancer cells.
BACKGROUND
Vitamin E analog, 2,5,7,8-tetramethyl-2R-(4R,8R, 12-trimethyltridecyl) chroman-6-yloxyacetic acid, referred to as alpha-TEA induces apoptosis in a variety of human cancer cells in cell culture and reduces tumor burden and metastases in preclinical animal models of breast and ovarian cancer. The goal of this study was to determine in vivo anticancer efficacy of alpha-TEA against human prostate cancer cells and identify mechanisms of action.


METHODS
A PC-3-GFP xenograft model was used to assess the effects of alpha-TEA formulated in liposomes and administered orally on tumor burden and metastases. Tumor tissue was examined by immunohistochemical staining for percentage of cells undergoing apoptosis by TUNEL or cell proliferation by Ki-67. In vitro analyses of mechanisms employed western immunoblotting to examine effects of alpha-TEA-treatments in LNCaP and PC-3-GFP cells on levels of pro-survival and pro-death factors. Functional significance was determined using ectopically expressed constitutively active forms, inhibitors, or siRNA.


RESULTS
alpha-TEA significantly reduced tumor burden and metastases, increased apoptosis and decreased proliferation of tumor cells (P < 0.05). alpha-TEA treatment of both LNCaP and PC-3-GFP cells in vitro reduced levels of pAkt1, pAkt2; FOXO1, c-FLIP(L) and survivin. Constitutively active Akt1, Akt2, c-FLIP or survivin reduced alpha-TEA-induced apoptosis. PI3K inhibitor enhanced apoptosis. Constitutively active FOXO1 enhanced alpha-TEA induced Fas ligand expression; whereas, FOXO1 siRNA reduced alpha-TEA induced Fas ligand expression.


CONCLUSIONS
alpha-TEA is an effective anticancer agent for human prostate cancer cells. Downregulation of pro-survival and upregulation of pro-death factors play roles in alpha-TEA-induced apoptosis.
Jia
Li
L
Section of Molecular Genetics and Microbiology, University of Texas at Austin, Austin, Texas, USA.
Yu
Weiping
W
Wang
Pei
P
Sanders
Bob G
BG
Kline
Kimberly
K
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077022:Survivin; D024505:Tocopherols / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002867:Chromones; C085126:FOXO1 protein, human; D053222:Fas Ligand Protein; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D009363:Neoplasm Proteins; D000077022:Survivin; D049452:Green Fluorescent Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; C488288:2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid; D024505:Tocopherols