An Oriental Herbal CAM modality for Prostate Cancer Chemoprevention

描述（由申请人提供）：我们的长期目标是从东方草药中开发一种用于前列腺癌（PCa）化学预防的口服有效、无毒的替代和补充药物（CAM）模式。我们已经发现由10种草药组成的甲米菊汤（KMKKT）的乙醇提取物（i）具有强的抗血管生成活性;（ii）抑制裸鼠中的人PC-3雄激素非依赖性PCa异种移植物的体内生长;（iii）抑制小鼠刘易斯肺癌同种异体移植物的体内生长;和（iv）抑制小鼠中的结肠癌肝转移。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。 鉴于癌发生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靶向多个分子靶点和细胞过程，这些靶点和细胞过程对癌症的发生、促进、进展和转移至关重要。我们假设：（a）KMKKT通过抗血管生成、细胞周期阻滞和促凋亡及抗转移作用，将是针对原发性前列腺癌发生的安全有效的CAM化学预防模式;和（B）可以鉴定出负责抗血管生成和抗转移活性的草药，以用最少数量的草药概括该配方。我们的具体目标1是评价口服KMKKT对原发性前列腺癌发生和转移的转基因腺癌小鼠前列腺（TRAMP）模型（Lu实验室）的化学预防功效。我们将比较口服给予KMKKT与腹膜内注射KMKKT对生殖泌尿（GU）道重量、背外侧前列腺（DLP）重量、腹侧前列腺（VP）和这些相应的叶中的病变进展（第1年），然后我们将确定在前列腺病变发展的不同阶段给予口服施用的KMKKT对TRAMP小鼠的长期存活的影响（1-2年级）。目的2是确定口服给药KMKKT的PCA相关的抗血管生成和抗转移活性，并通过单一草药缺失方法结合个体草药评价（Kim Lab）鉴定每种活性的活性草药。目标1中口服KMKKT混合物具有积极的化学预防功效且无毒性，这将极大地推动其持续临床前开发，为规划人类转化研究铺平道路。目标2的成功实现将使我们能够确定，在未来，是否可以用最少数量的草药来概括完整配方的化学预防作用。已鉴定的草药将是鉴定活性化学物质的极好起点，用于草药CAM产品的更好QC/QA以及进一步的药理学研发。 公共卫生相关性：前列腺癌（PCa）是美国男性癌症死亡的第二大原因。尽管在早期检测和治疗方面取得了进展，但对于晚期和转移性疾病仍然没有治愈方法。化学预防已被公认为是一种合理的和具有成本效益的替代方法，以减少PCa的发病率和死亡率。然而，由于癌发生的复杂性，主流的单剂/靶点研究至今尚未导致任何有效的PCa化学预防模式的发展。该R21应用程序特别关注测试具有可证明的多靶向抗癌活性的东方草药配方，以支持实现该目标的范式转变。

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.