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口服有效、无毒的替代药物(CAM)用于前列腺癌(PCA)的化学预防。我们发现，由10种中草药组成的甲米康葛汤乙醇提取物(KMKKT)具有很强的抗血管生成活性；(Ii)抑制人PC-3雄激素非依赖性PCa裸鼠移植瘤的体内生长；(Iii)抑制小鼠Lewis肺癌同种异体移植瘤的生长；(Iv)抑制小鼠结肠癌-肝转移。重要的是，KMKKT在测试剂量下观察到了上述效果，对体重没有不良影响，支持了其长期使用的极佳安全性。鉴于癌症的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针对多个分子靶点和细胞过程，这些分子和细胞过程对癌症的启动、促进、进展和转移至关重要。我们假设：(A)抗前列腺癌胶囊通过抗血管生成、细胞周期停滞、促凋亡和抗转移作用，是一种安全有效的预防前列腺癌的化学预防方法；(B)可以确定具有抗血管生成和抗转移活性的中药(S)，用最少的中药来概括这一公式。我们的具体目的1是评价口服KMKKT对转基因小鼠前列腺癌(TRAMP)原发前列腺癌发生和转移模型(Lu LAB)的化学预防效果。我们将比较口服KMKKT和ip的效果。注射KMKKT对生殖器尿路(GU)重量、前列腺背外侧(DLP)重量、腹侧前列腺(VP)和这些叶的病变进展(第1年)的影响，然后我们将确定在前列腺病变发展的不同阶段给予KMKKT对不稳定小鼠(第1-2年)长期生存的影响。目的2确定口服KMKKT的PCA相关的抗血管生成和抗转移活性，并通过单草药缺失法结合个别草药评价(Kim Lab)确定每种活性的活性草药。在AIM 1中，口服KMKKT鸡尾酒具有积极的化学预防效果，且无毒性，将极大地推动其继续临床前开发，为计划人类翻译研究铺平道路。目标2的成功实现将使我们能够在未来确定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。已确定的草药将是识别活性化学物质的极佳起点，以更好地进行草药CAM产品的QC/QA以及进一步的药理研究和开发。 与公共健康相关：前列腺癌(PCA)是美国男性癌症死亡的第二大原因。尽管在早期发现和治疗方面取得了进展，但晚期和转移性疾病尚无治愈方法。化学预防已被认为是降低PCa发病率和死亡率的一种合理且经济有效的替代方法。然而，由于致癌过程的复杂性，主流的单剂/靶向研究尚未导致任何有效的PCa化学预防模式的发展。这个R21应用程序特别专注于测试一种东方草药配方，该配方具有明显的多靶向抗癌活性，以支持实现这一目标的范式转变。

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.