Basu Arpita, Grossie Bruce, Bennett Michael, Mills Nat, Imrhan Vicky
Nutritional Sciences, 301 Human Environmental Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
Eur J Nutr. 2007 Feb;46(1):34-43. doi: 10.1007/s00394-006-0629-4. Epub 2006 Dec 15.
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.
前列腺癌是美国和欧洲癌症相关死亡的主要原因之一。琥珀酸α-生育酚（α-TOS）已被证明可通过多种机制在体外抑制人前列腺癌生长，包括抑制前列腺特异性抗原（PSA）和血管内皮生长因子（VEGF）的表达。α-TOS的给药途径对其抗肿瘤活性有深远影响，很少有研究调查其对体内前列腺癌生长的影响。
本研究检验了这样一个假设，即与接受赋形剂的对照组相比，α-TOS通过调节肿瘤组织中PSA和VEGF基因表达，可降低喂食低（7%）和高（20%）水平膳食大豆油的小鼠体内人前列腺LNCaP肿瘤的生长。
将42只BALB/c裸鼠皮下接种1×10⁶个LNCaP细胞，并分为四个饮食组之一；含或不含α-TOS处理的7%或20%大豆油饮食组。三周后，小鼠每天腹腔注射溶于芝麻油（SSO）的α-TOS（100mg/kg体重），持续两周；对照组接受SSO注射。每周记录肿瘤体积。在七周时收集血清、肝脏和肿瘤组织，用于血清PSA、睾酮和α-生育酚分析、组织病理学检查以及肿瘤中PSA和VEGF基因片段的逆转录和聚合酶链反应（RT-PCR）扩增。使用实时PCR进行基因表达的相对定量。P≤0.05被认为具有统计学意义。
与对照组相比，腹腔注射α-TOS使两组（7%和20%脂肪组）的肿瘤生长均减缓（P<0.05）。与接受SSO处理的对照组相比，α-TOS处理显著降低了血清PSA和睾酮水平（P<0.05）。如充血血管数量更多所示，对照肿瘤的血管生成程度高于α-TOS处理的肿瘤。α-TOS处理也降低了PSA和VEGF mRNA表达（P<0.05），揭示了α-TOS抑制LNCaP异种移植瘤生长的可能分子机制。
我们的研究表明，与对照组相比，在喂食低（7%）和高（20%）脂肪大豆油饮食的裸鼠中，α-TOS处理可显著降低LNCaP异种移植瘤的生长。给予α-TOS可显著降低血清PSA和睾酮水平、肿瘤血管生成以及PSA和VEGF mRNA表达，这表明α-TOS可能作为一种化疗药物用于人类前列腺癌，值得进一步研究其在人体内的剂量和给药方式。
