Therapeutic effect of boswellin in prostate cancer

描述（由申请人提供）：前列腺癌是美国男性死亡的第二大原因。目前前列腺癌的辅助治疗方式，激素消融和内分泌治疗，往往导致暂时的收益，随后在治疗后1-2年内疾病复发。因此，迫切需要确定分子靶点，这可能导致疾病管理的长期收益。前列腺癌已被证实过度表达5-脂氧合酶（5-LOX）。已发现5-LOX的产物5-羟基二十碳四烯酸（5-HETE）和5-氧- 6e， SZ, 11Z， 14z -二十碳四烯酸（5-oxETE）是细胞存活因子，阻断这些产物的合成可导致细胞凋亡。因此，5-LOX是前列腺癌治疗的潜在分子靶点。我们发现前列腺癌细胞对乳香酸（一种从乳香菌和塞拉菌中分离的纯5-LOX抑制剂）诱导的细胞生长抑制和凋亡敏感。乳香素是一种含有20%乳香酸的粗甲醇提取物，目前在美国被用作抗关节炎和抗炎的补充药物。我们假设前列腺癌对boswell -in诱导的细胞凋亡的生长抑制高度敏感。1)研究boswell蛋白及其成分对前列腺癌细胞和正常前列腺上皮细胞生长的抑制作用和诱导凋亡的作用。通过比较5-LOX活性和细胞对boswellin诱导的生长抑制的敏感性，我们将检验boswellin诱导的细胞凋亡与5-LOX抑制之间的联系。2)确定boswell蛋白在临床前动物模型中的疗效。将分别在小鼠和大鼠身上进行急性和亚慢性毒性试验。肿瘤生长抑制和细胞凋亡诱导，然后使用确定的剂量不会造成不可忍受的毒性。我们希望我们的建议将导致发现一种新的补充剂前列腺癌的治疗。

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of male death in the United States. The current adjuvant treatment modalities for prostate cancer, hormone ablation and endocrine therapy, often lead to temporary gains, which are followed by disease relapse within as little as 1-2 years post-treatment. Therefore, there is a pressing need to identify molecular targets, which may lead to longer-lived gains in disease management. Prostate cancers have been shown to over express 5-lipoxygenase (5-LOX). 5-hydroxyeicosatetraenoic acid (5-HETE) and 5-oxo-6E, SZ, 11Z, 14Z-eicosatetraenoic acid (5-oxETE), the products of 5-LOX, have been found to be cell survival factors and blocking the synthesis of these products leads to cell apoptosis. Thus 5-LOX is a potential molecular target for prostate cancer treatment. We have found that prostate cancer cells are sensitive to boswellic acid (a pure 5-LOX inhibitor isolated from Boswellia carterri and serrata) -induced cell growth inhibition and apoptosis. Boswellin, a crude methanol extract containing 20% boswellic acids, is currently used as a complementary anti-arthritic and anti-inflammatory pharmacological agent in the US. We hypothesize that prostate cancer will be highly sensitive to Boswellin-induced growth inhibition via apoptosis. We propose 1) to investigate cell growth inhibition and apoptosis induction by Boswellin and its ingredients among prostate cancer cells and normal prostate epithelial cells. The connection between Boswellin-induced apoptosis and 5-LOX inhibition will be tested by comparing 5-LOX activity and cell sensitivity to Boswellin-induced growth inhibition. 2) To determine the efficacy of Boswellin in preclinical animal models. Acute and subchronic toxicity will be tested in mice and rats, respectively. Tumor growth inhibition and apoptosis induction will then be measured using doses determined not to cause untolerable toxicity. We hope our proposal will lead to the discovery of a novel complementary agent for prostate cancer treatment.