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。目前的前列腺癌辅助治疗方式，激素消融和内分泌治疗，往往导致暂时的收益，这是随后的疾病复发在短短1-2年治疗后。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。前列腺癌已经显示过表达5-脂氧合酶（5-LOX）。5-已发现5-LOX的产物5-羟基二十碳四烯酸（5-HETE）和5-氧代-6E，SZ，11 Z，14 Z-二十碳四烯酸（5-oxETE）是细胞存活因子，并且阻断这些产物的合成导致细胞凋亡。因此，5-LOX是前列腺癌治疗的潜在分子靶点。我们已经发现前列腺癌细胞对乳香酸（一种从乳香属（Boswellia carterri）和乳香属（Serrata）分离的纯5-LOX抑制剂）诱导的细胞生长抑制和凋亡敏感。乳香林是一种含有20%乳香酸的粗甲醇提取物，目前在美国被用作补充性抗关节炎和抗炎药理剂。我们推测前列腺癌对乳香素通过细胞凋亡诱导的生长抑制高度敏感。我们提出1）研究乳香素及其成分对前列腺癌细胞和正常前列腺上皮细胞的生长抑制和凋亡诱导作用。通过比较5-LOX活性和细胞对乳香素诱导的生长抑制的敏感性来测试乳香素诱导的细胞凋亡和5-LOX抑制之间的联系。2)确定Boswelin在临床前动物模型中的疗效。将分别在小鼠和大鼠中测试急性和亚慢性毒性。然后使用确定不会引起不可耐受毒性的剂量测量肿瘤生长抑制和细胞凋亡诱导。我们希望我们的建议将导致发现一种新的补充剂治疗前列腺癌。

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.