Direct targeting of cancer invasion and metastasis using Withania root extracts

描述（由申请人提供）：虽然临床医生可以预测哪些患者有发生转移的风险，但传统疗法证明无效，转移性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。波形蛋白过表达在基础和临床前模型中几乎所有的侵袭性癌症中被发现，并且被用作癌症侵袭的临床标志物。功能研究表明，波形蛋白是细胞迁移所必需的，但不是生存能力，过度表达导致更具侵略性和能动性的癌细胞。在这里，我们提出的数据表明，睡茄根提取物（WRE）的目标波形蛋白抑制癌细胞的运动和入侵，而在低剂量的细胞活力的影响可以忽略不计。我们测试的假设，WRE是一种抗转移和抗侵入性的补充替代药物（CAM），破坏波形蛋白的功能，毒性有限。我们提出全面分析WRE在细胞系和临床前转移小鼠模型中的抗侵袭和抗转移功效。我们将采用最先进的活细胞成像来剖析WRE如何抑制波形蛋白功能和癌细胞迁移的机制，以及确定WRE是否抑制内皮细胞运动，从而产生抗血管生成活性。由于所有数据表明波形蛋白破坏不影响细胞活力，因此这种细胞侵袭抑制剂与CAM和化学预防的目标一致。最终，我们设想WRE可以成为高风险转移性患者的一种靶向波形蛋白的化学预防剂。 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，大多数治疗针对原发性肿瘤而不是转移。在这里，我们采取化学预防方法来防止癌症侵袭和转移的发生。我们提出了研究我们的新化合物的疗效，其作用机制和临床前活性的研究。

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.