Chemopreventive effects of dietary cottonseed oil

描述（由申请人提供）： 棉酚（GP）是存在于棉籽中的天然多酚类色素 产品，如棉籽油（CSO），由人类消费， 食用动物。GP的抗癌活性是有据可查的 在我们的实验室和其他人。 我们已发表的初步结果显示：（a）GP减少了原发性肿瘤 哥本哈根大鼠的生长和肺和淋巴结转移 MAT-LyLu Dunning前列腺癌细胞;（B）GP-诱导的前列腺癌细胞中的细胞周期停滞 PC-3细胞和培养的人BPH细胞与升高的TGF-β相关;（c） GP抑制MAT-LyLu细胞的体外侵袭活性; 胚胎绒毛尿囊膜实验提示GP抑制血管生成; (e)一种新的MAT-LyLu亚系已经从转移的肺中分离出来， 携带MAT-LyLu的哥本哈根大鼠（MLL细胞）表现出更大的侵袭性， nm 23转移抑制基因的能力和较低的mRNA水平;和（f）CSO 对PC-3细胞具有极强的抗增殖活性， 体外然而，通过消费GP摄入的潜在生物医学益处 含有CSO的食品的安全性尚未报告。我们的目标是 评价食用含CSO的实验饮食对 携带MAT-LyLu或MLL细胞的Copenhagen大鼠的肿瘤生长和转移 深入了解CSO作为饮食化学预防剂的潜在效用 或前列腺癌的治疗剂。研究的具体目标是 以：（1）确定是否食用含有CSO的实验饮食 将预防和/或抑制哥本哈根大鼠中的肿瘤生长和转移 携带MAT-LyLu或MLL肿瘤：（2）确定是否消耗 含有CSO的饮食诱导TGF-13和nm 23的表达水平升高 转移抑制基因，和/或降低微血管密度作为衡量 携带MAT-LyLu和MLL的哥本哈根原发性肿瘤内的血管生成 （3）比较MAT-LyLu和新分离的MLL的体内行为 细胞在哥本哈根大鼠中的肿瘤生长和转移;和（4） 评估消费含CSO的食品所产生的潜在毒性 节食。将饲喂用不同水平的CSO配制的实验饮食 皮下植入MAT-LyLu或MLL的雄性哥本哈根大鼠 细胞喂食将在相对于出生日的不同时间开始开始 置入在研究过程中将监测肿瘤生长。 肿瘤大小、TGF-β和nm 23的肿瘤水平、睾酮的血清水平， TGF-b蛋白和LDH活性、肿瘤微血管密度和GP水平 将测定收集的组织。我们建议的研究结果可能 确定可用于预防的饮食成分 前列腺癌细胞生长和转移。拟议的研究将作为一项 饮食CSO用于治疗糖尿病的临床前基础 预防和抑制人前列腺癌生长和/或 转移

DESCRIPTION (provided by applicant): Gossypol (GP) is a natural polyphenolic pigment present in cottonseed products, such as cottonseed oil (CSO), that are consumed by humans and food-producing animals. The anticancer activities of GP are well-documented by research in our laboratory and others. Our published and preliminary results reveal: (a) GP reduced primary tumor growth and metastases to lungs and lymph nodes in Copenhagen rats bearing MAT-LyLu Dunning prostate cancer cells; (b) GP-induced cell cycle arrest in PC-3 cells and cultured human BPH cells is associated with elevated TGF-B; (c) GP inhibited the in vitro invasive activity of MAT-LyLu cells; (d) the chick embryo chorioallantoic membrane assay suggested that GP inhibits angiogenesis; (e) a novel MAT-LyLu subline has been isolated from the metastasized lungs of MAT-LyLu-bearing Copenhagen rats (MLL cells) which exhibit greater invasive ability and lower mRNA levels of nm23 metastasis suppressor gene; and (f) CSO possesses extremely potent antiproliferative activity against PC-3 cells in vitro. However, the potential biomedical benefits of GP intake via consumption of CSO-containing food products has not been reported. Our objective is to evaluate the effect of the consumption of CSO-containing experimental diets on tumor growth and metastasis in Copenhagen rats bearing MAT-LyLu or MLL cells to gain insight into the potential utility of CSO as a dietary chemopreventive or therapeutic agent for prostate cancer. The specific aims of the study are to: (1) determine whether consumption of CSO-containing experimental diets will prevent and/or inhibit tumor growth and metastasis in Copenhagen rats bearing MAT-LyLu or MLL tumors: (2) determine whether consumption of CSO-containing diets induces elevates expression levels of TGF-I3 and nm23 metastasis suppressor gene, and/or reduces microvessel density as a measure of angiogenesis within primary tumors of MAT-LyLu- and MLL-bearing Copenhagen rats; (3) compare the in vivo behaviors of MAT-LyLu and the newly isolated MLL cells with respect to tumor growth and metastasis in Copenhagen rats; and (4) evaluate the potential toxicity resulting from consumption of CSO-containing diets. Experimental diets formulated with different levels of CSO will be fed to male Copenhagen rats bearing subcutaneous implants of MAT-LyLu or MLL cells. Feeding will begin at different times relative to the day of implantation. Tumor growth will be monitored during the course of the study. Tumor size, tumor levels of TGF-P and nm23, serum levels of testosterone, TGF-b protein and LDH activity, tumor microvessel density, and GP levels in collected tissues will be determined. The findings of our proposed study may identify a dietary component that can be exploited for the prevention of prostate cancer cell growth and metastasis. The proposed study will serve as a preclinical basis for future clinical trials of the utility of dietary CSO for the prevention and inhibition of human prostate cancer growth and/or metastasis.