Direct targeting of cancer invasion and metastasis using Withania root extracts

描述(申请人提供)：尽管临床医生可以预测哪些患者有发生转移的风险，但传统疗法被证明是无效的，转移疾病是癌症患者死亡的主要原因。我们提出了一种新的抗转移策略，通过干扰一个独特的细胞迁移靶点--波形蛋白细胞骨架来防止转移的发生。在基础和临床前模型中，几乎所有的浸润性癌中都存在波形蛋白的过度表达，并被用作肿瘤侵袭的临床标志。功能研究表明，波形蛋白对细胞迁移是必不可少的，但不是活性所必需的，过度表达会导致癌细胞更具侵袭性和运动性。在这里，我们提出的数据表明，薇菜根提取物(WRE)靶向波形蛋白，以抑制癌细胞的运动和侵袭，而在低剂量时对细胞活力的影响可以忽略不计。我们测试了WRE是一种抗转移和抗侵袭的补充替代药物(CAM)的假设，它以有限的毒性扰乱波形蛋白功能。我们提出了对WRE在细胞系和临床前转移小鼠模型中的抗侵袭和抗转移有效性的综合分析。我们将使用前沿的活细胞成像技术来剖析WRE如何抑制Vimentin功能和癌细胞迁移的机制，并确定WRE是否抑制内皮细胞的运动从而抑制血管生成活性。由于所有数据表明，波形蛋白的破坏不会影响细胞的活性，这种细胞侵袭抑制物符合CAM和化学预防的目标。最终，我们设想WRE可以成为高危转移患者中以波形蛋白为靶点的化学预防药物。 公共卫生相关性：转移性疾病是几乎所有癌症类型的主要死亡原因；然而，大多数治疗针对的是原发肿瘤而不是转移。在这里，我们采取化学预防的方法来防止癌症的侵袭和转移。我们建议进行研究，调查我们的新化合物的有效性，其作用机制，以及临床前活性。

DESCRIPTION (provided by applicant): Though clinicians can predict which patients are at risk for developing metastases, traditional therapies prove ineffective and metastatic disease is the primary cause of cancer patient death. We propose a novel anti- metastatic strategy to prevent metastases from occurring by perturbing a unique cell migration target-the vimentin cytoskeleton. Vimentin overexpression is found in nearly all invasive cancers in both basic and pre- clinical models, and is used as a clinical marker of cancer invasion. Functional studies show that vimentin is essential for cell migration but not viability, and overexpression leads to more aggressive and motile cancer cells. Here we present data showing that Withania somnifera root extracts (WRE) target vimentin to inhibit cancer cell motility and invasion while having negligible effects on cell viability at low doses. We test the hypothesis that WRE is an anti-metastatic and anti-invasive complementary alternative medicine (CAM) that disrupts vimentin function with limited toxicity. We propose comprehensive analysis of the anti-invasive and anti-metastatic efficacy of WRE in cell lines and a pre-clinical metastatic mouse model. We will employ cutting- edge live cell imaging to dissect the mechanism of how WRE inhibits vimentin function and cancer cell migration, as well as determine if WRE inhibits endothelial cell motility resulting in anti-angiogenic activity. Since all data show that vimentin disruption does not impact cell viability, this cell invasion inhibitor is aligned with the goals of CAM and chemoprevention. Ultimately, we envision that WRE can be a vimentin-targeting chemopreventative in high-risk metastatic patients. PUBLIC HEALTH RELEVANCE: Metastatic disease is the major cause of death in almost all cancer types; however, most treatments target the primary tumor and not the metastases. Here we take a chemopreventative approach to prevent cancer invasion and metastasis from ever occurring. We propose studies that investigate the efficacy of our novel compound, its mechanism of action, and pre-clinical activity.