An Oriental Herbal CAM modality for Prostate Cancer Chemoprevention

描述（由申请人提供）：我们的长期目标是开发一种口服有效，无毒的东方草药替代和补充药物（CAM）模式，用于前列腺癌（PCa）的化学预防。我们发现，由10种草本植物组成的加蜜开桂汤乙醇提取物（KMKKT）具有较强的抗血管生成活性；（ii）在裸鼠体内抑制人PC-3雄激素非依赖性PCa异种移植物的生长；（iii）抑制小鼠Lewis肺癌异体移植物的体内生长；（iv）抑制小鼠结肠癌-肝转移。重要的是，在测试剂量下，观察到KMKKT的上述作用对体重没有不良影响，支持其长期使用的良好安全性。鉴于癌变是一个多阶段的过程，需要许多遗传和表观遗传改变，有效的预防措施必须选择性地针对癌症发生、促进、进展和转移的多个重要分子靶点和细胞过程。我们假设(a) KMKKT将是一种安全有效的CAM化学预防方式，通过抗血管生成、细胞周期阻滞、促凋亡和抗转移的作用来预防原发性前列腺癌；(b)可以确定具有抗血管生成和抗转移活性的草药，从而用最少数量的草药概括该公式。我们的具体目的1是评估口服KMKKT对转基因腺癌小鼠前列腺（TRAMP）原发性前列腺癌发生和转移模型的化学预防作用（Lu实验室）。我们将比较口服给药KMKKT与静脉注射KMKKT对泌尿生殖道（GU）重量、前列腺背外侧（DLP）重量、前列腺腹侧（VP）和病变进展的影响（1年），然后我们将建立在前列腺病变发展的不同阶段口服KMKKT对TRAMP小鼠长期生存的影响（1-2年）。目的2是确定口服KMKKT与pca相关的抗血管生成和抗转移活性，并通过单一草药缺失法结合单个草药评估确定每种活性的活性草药（Kim Lab）。在Aim 1中，口服KMKKT鸡尾酒具有积极的化学预防功效，而且没有毒性，这将极大地推动其继续进行临床前开发，为规划人体转化研究铺平道路。目标2的成功实现将使我们将来能够确定，整个方案的化学预防作用是否可以用最少数量的草药来概括。已鉴定的草药将是鉴定活性化学物质的良好起点，可以更好地进行草药CAM产品的QC/QA以及进一步的药理学研发。

DESCRIPTION (provided by applicant): Our long term goal is to develop an orally effective, non-toxic alternative and complimentary medicine (CAM) modality from Oriental herbs for prostate cancer (PCa) chemoprevention. We have found that the ethanol extract of Ka-mi-kae-kyuk-tang (KMKKT) consisting of 10 herbs (i) has strong anti-angiogenesis activity; (ii) inhibits the in vivo growth of human PC-3 androgen-independent PCa xenografts in nude mice; (iii) inhibits the in vivo growth of mouse Lewis lung carcinoma allograft; and (iv) inhibits colon cancer-liver metastasis in the mice. And importantly, the above effects of KMKKT were observed without adverse effects on body weight at the doses tested, supporting its excellent safety for long-term use. Given that carcinogenesis is a multi-stage process requiring many genetic and epigenetic alterations, effective preventive measures must selectively target multiple molecular targets and cellular processes important for cancer initiation, promotion, progression and metastasis. We hypothesize that (a) KMKKT will be a safe and effective CAM chemopreventive modality against primary prostate carcinogenesis through anti- angiogenic, cell cycle arrest and pro-apoptotic and anti-metastasis actions; and (b) the herb(s) responsible for the anti-angiogenesis and anti-metastasis activity can be identified to recapitulate this formula with a minimal number of herbs. Our specific aim 1 is to evaluate the chemopreventive efficacy of orally-administered KMKKT against the transgenic adenocarcinoma mouse prostate (TRAMP) model of primary prostate carcinogenesis and metastasis (Lu lab). We will compare the effect of orally-administered KMKKT vs. i.p. injection of KMKKT on genito-urinary (GU) tract weight, dorsolateral prostate (DLP) weight, ventral prostate (VP) and lesion progression in these respective lobes (Year 1) and then we will establish the impact of orally- administered KMKKT given at different stages of prostate lesion development on the long term survival of the TRAMP mice (Year 1-2). Aim 2 is to determine the PCa-relevant anti-angiogenesis and anti-metastasis activities of orally-administered KMKKT and identify active herbs for each activity through a single-herb deletion approached combined with individual herbal evaluation (Kim Lab). Positive chemopreventive efficacy without toxicity with the orally-administered KMKKT cocktail in Aim 1 will be a great impetus for its continued preclinical development to pave the way for planning human translational studies. Successful accomplishment of Aim 2 will enable us to determine, in the future, whether the chemopreventive action of the full formula can be recapitulated by a minimal number of herbs. The identified herbs will be excellent starting points to identify active chemicals for better QC/QA of the herbal CAM products as well as for further pharmacological R&D. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) is the No. 2 cause of cancer death of men in the US. In spite of the advances in early detection and treatments, there is no cure for the late stage and metastatic disease. Chemoprevention has become recognized as a plausible and cost-effective alternative approach to reduce the morbidity and mortality of PCa. However, due to the complex nature of carcinogenesis, main stream single agent/target-based research has not led to the development of any effective chemopreventive modality for PCa so far. This R21 application specifically focuses on testing an Oriental herbal formula with demonstrable multiple targeting anti- cancer activities to support a paradigm shift to achieve that goal.