Alpha-tocopheryl succinate (alpha-TOS) modulates human prostate LNCaP xenograft growth and gene expression in BALB/c nude mice fed two levels of dietary soybean oil.
BACKGROUND
Malignancy of the prostate constitutes a leading cause of cancer-related deaths in America and Europe. Alpha-tocopheryl succinate (alpha-TOS) has been shown to inhibit human prostate cancer growth in vitro, via several mechanisms, including inhibiting prostate-specific antigen (PSA) and vascular endothelial growth factor (VEGF) expressions. The route of alpha-TOS administration has a profound effect on its antitumor activity, and few studies have investigated its effects on prostate cancer growth in vivo.


OBJECTIVE
The present study tested the hypothesis that alpha-TOS wil reduce the growth of human prostate LNCaP tumors in mice fed low (7%) and high (20%) levels of dietary soybean oil, compared to the controls receiving vehicle, by modulating PSA and VEGF gene expressions in the tumor tissue.


METHODS
BALB/c nude mice (n = 42) were subcutaneously inoculated with 1 x 10(6) LNCaP cells and assigned to one of four dietary groups; 7% or 20% soybean oil diet with or without alpha-TOS treatment. Three weeks later, mice received daily intraperitoneal injections of alpha-TOS (100 mg/kg body weight) in sesame seed oil (SSO) for two weeks; controls received SSO injections. Tumor volumes were recorded weekly. Sera, liver, and tumor tissues were collected at seven weeks for serum PSA, testosterone and alpha-tocopherol analyses, histopathological examination, and reverse transcription and polymerase chain reaction (RT-PCR) amplification of PSA and VEGF gene fragments in tumors. Relative quantification of gene expression was performed using real-time PCR. P < or = 0.05 was considered significant.


RESULTS
Intraperitoneal injections of alpha-TOS caused decreased tumor growth in both groups (7% and 20% fat, P < 0.05), versus controls. alpha-TOS treatment significantly reduced serum PSA and testosterone levels in comparison to the SSO-treated controls (P < 0.05). Control tumors had a greater degree of angiogenesis than alpha-TOS tumors, as demonstrated by the greater number of blood-filled vessels. PSA and VEGF mRNA expressions, were also reduced with alpha-TOS treatment (P < 0.05), revealing the possible molecular mechanisms of growth inhibition of LNCaP xenografts by alpha-TOS.


CONCLUSIONS
Our study shows significant reduction in LNCaP xenograft growth with alpha-TOS treatment in nude mice fed a low (7%) and high (20%) fat soybean oil diets versus controls. Serum PSA and testosterone, tumor angiogenesis, and PSA and VEGF mRNA expressions were markedly reduced by alpha-TOS administration, suggesting a possible role of alpha-TOS as a chemotherapeutic agent in human prostate cancer, and warrants further investigations on the dose and delivery of alpha-TOS in humans.
Basu
Arpita
A
Nutritional Sciences, 301 Human Environmental Sciences, Oklahoma State University, Stillwater, OK 74078, USA. arpita.basu@okstate.edu
Grossie
Bruce
B
Bennett
Michael
M
Mills
Nat
N
Imrhan
Vicky
V
D000818:Animals; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D013024:Soybean Oil / Q000008:administration & dosage*; D013739:Testosterone / Q000097:blood; D024505:Tocopherols; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D042461:Vascular Endothelial Growth Factor A; D014810:Vitamin E; D013739:Testosterone; D013024:Soybean Oil; D017430:Prostate-Specific Antigen; D024505:Tocopherols