Alpha-tocopheryl succinate (α-TOS) modulates human prostate LNCaP xenograft growth and gene expression in BALB/c nude mice fed two levels of dietary soybean oil

Abstract

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. 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. 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. 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. 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.