Therapeutic effect of boswellin in prostate cancer

描述(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，往往会导致暂时的收益，随后在治疗后短短1-2年内疾病复发。因此，迫切需要确定分子靶点，这可能会在疾病管理方面带来更长期的收益。前列腺癌被证明过度表达5-脂氧合酶(5-LOX)。5-LOX的产物5-羟基二十碳四烯酸(5-HETE)和5-氧代-6E，SZ，11Z，14Z-二十碳四烯酸(5-oxETE)是细胞的生存因子，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，前列腺癌细胞对博斯威酸(一种从乳香和锯齿草中分离出来的纯5-LOX抑制剂)诱导的细胞生长抑制和凋亡非常敏感。博斯韦林是一种含有20%博士林酸的粗甲醇提取物，目前在美国被用作抗关节炎和消炎的补充药理药剂。我们假设前列腺癌对Boswell in通过细胞凋亡诱导的生长抑制高度敏感。我们建议1)研究博斯韦林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诱导凋亡作用。将通过比较5-LOX活性和细胞对Boswell in诱导的生长抑制的敏感性来测试Boswell in诱导的细胞凋亡和5-LOX抑制之间的联系。2)观察博斯韦林对临床前动物模型的疗效。急性毒性和亚慢性毒性将分别在小鼠和大鼠身上进行测试。然后，将使用确定不会造成不可耐受毒性的剂量来衡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用于前列腺癌治疗的新的补充药物。

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.