Ashwagandha supplementation enhances ovarian tumoricidal activity of NK cells

Ashwagandha 补充剂增强 NK 细胞的卵巢肿瘤杀伤活性

• 批准号: 8823170
• 负责人: Animesh Barua
• 金额: $ 21.41万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-09 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8823170
• 关键词: 4 year old; Abdominal Cavity; Activated Natural Killer Cell; Acute; Animal Model; Animals; Ashwagandha; Binding; Cancer Patient; Cell physiology; Cell surface; Cells; Cellular Stress; Cessation of life; Cherry - dietary; Chickens; Chronic Disease; Chronic stress; Clear Cell; Cleaved cell; Clinical Research; Control Groups; Death Rate; Development; Diagnosis; Diet; Dietary Supplementation; Diffusion; Disease; Disease Progression; Early Diagnosis; Effectiveness; Exposure to; Frequencies; Glucose; Goals; Greater sac of peritoneum; Health Care Costs; Herb; Human; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Incidence; Infiltration; Inflammation; Inflammatory; Intra-abdominal; Lead; Length; Ligands; Major Histocompatibility Complex; Malignant - descriptor; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Medicinal Plants; Microscopic; Molecular; Molecular Chaperones; Monitor; Mucinous; Names; Natural Immunity; Natural Killer Cells; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Ovarian; Ovarian Tissue; Ovary; Patients; Peritoneal; Pharmaceutical Preparations; Phase; Plant Roots; Play; Powder dose form; Pre-Clinical Model; Prevention; Preventive; Proteins; Recurrence; Role; Sampling; Scanning; Serous; Serum; Solid; Staging; Supplementation; Surface; Survival Rate; Symptoms; Testing; Tissues; Traditional Medicine; Translating; Transvaginal Ultrasound; Tumor Escape; Tumor-Derived; Ultrasonography; Woman; age group; antitumor effect; base; cancer cell; cancer initiation; cell type; cohort; cytotoxic; egg; emergency service responder; feeding; immune function; improved; in vivo; innate immune function; killings; member; neoplastic cell; novel; ovarian cancer prevention; ovarian neoplasm; pre-clinical; prevent; prophylactic; public health relevance; receptor; stressor; success; tumor; tumor growth; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Ovarian cancer (OVCA) is a fatal malignancy of women with highest case to death ratio among gynecological cancers. OVCA differs from other malignancies that it mainly disseminates locally in the peritoneal and abdominal cavity. Thus, factors in tumor microenvironment play critical roles in tumor progression as well as prevention of OVCA metastasis. Innate immune cells are members of tumor microenvironment and first responders to a developing tumor. However, tumor suppresses anti-tumor immune responses by secreting immunosuppressive factors, which in most cases, shift anti-tumor functions of innate immune cells to pro-tumor roles favoring tumor growth. Natural killer (NK) cells are a member of innate immunity with cytotoxic functions necessary to eliminate a growing tumor. However, our preliminary studies showed that progression of ovarian tumors to late stages was associated with the inhibition of NK cell infiltration to the tumor vicinity. Our preliminary studis further showed that this tumor-induced inhibition of intra-tumor NK cell infiltration was mediated by shedding of major histocompatibility complex class I related chain A (MICA) expressed on the surface of malignant cells. MICA is a ligand of NK cell receptor NKG2D. Upon binding with MICA, NKG2D activates NK cells for cytotoxic activities. Shedding of MICA by the tumor from its surface prevents NK cells to recognize the tumor cells, thus, the tumor escapes cytotoxic effects of NK cells. Dietary supplementation of hens (with or without OVCA) with Ashwagandha root powder in our preliminary study showed inhibition of tumor progression and reduced incidence of new OVCA cases. Ashwagandha is an herb used in traditional medicine as anti-stressor and inflammatory agent. Proposed study seeks to confirm these preliminary observations in a large cohort of hens by two Specific Aims. Aim 1 will determine the efficacy of Ashwagandha in increasing the influx of intra-tumoral NK cells and thus enhancing ovarian tumoricidal role of NK cells. Aim 2 will determine the length of exposure to dietary Ashwagandha supplementation required to maintain a long- term anti-tumor activities of NK cells. Successful accomplishment of the proposed study will generate noble information and will be helpful for a longer study and/or an early phase clinical study to examine the role of Ashwagandha in enhancing ovarian tumoricidal functions of NK cells.

描述（由申请人提供）：卵巢癌（OVCA）是妇科癌症中死亡率最高的女性致命恶性肿瘤。OVCA与其他恶性肿瘤不同，它主要在腹膜和腹腔局部播散。因此，肿瘤微环境中的因素在肿瘤进展以及预防OVCA转移中起关键作用。先天免疫细胞是肿瘤微环境的成员，也是发展中肿瘤的第一反应者。然而，肿瘤通过分泌免疫抑制因子来抑制抗肿瘤免疫应答，这在大多数情况下将先天免疫细胞的抗肿瘤功能转变为有利于肿瘤生长的促肿瘤作用。自然杀伤（NK）细胞是先天免疫的成员，具有消除生长中的肿瘤所必需的细胞毒性功能。然而，我们的初步研究表明，卵巢肿瘤进展到晚期与NK细胞浸润到肿瘤附近的抑制有关。我们的初步研究进一步表明，这种肿瘤诱导的肿瘤内NK细胞浸润的抑制是由恶性细胞表面表达的主要组织相容性复合物I类相关链A（云母）的脱落介导的。云母是NK细胞受体NKG 2D的配体。与云母结合后，NKG 2D激活NK细胞的细胞毒性活性。肿瘤从其表面脱落云母阻止NK细胞识别肿瘤细胞，因此，肿瘤逃避NK细胞的细胞毒性作用。在我们的初步研究中，用Ashwagandha根粉对母鸡（有或没有OVCA）进行饮食补充显示出肿瘤进展的抑制和新OVCA病例的发生率降低。Ashwagandha是一种草药，在传统医学中用作抗应激剂和炎症剂。拟议的研究旨在通过两个特定目的在一个大型母鸡队列中证实这些初步观察结果。目的1将确定Ashwagandha在增加肿瘤内NK细胞的流入从而增强NK细胞的卵巢杀肿瘤作用中的功效。目的2将确定暴露于饮食Ashwagandha补充剂的时间长度，以维持NK细胞的长期抗肿瘤活性。拟议研究的成功完成将产生宝贵的信息，并将有助于更长时间的研究和/或早期临床研究，以检查Ashwagandha在增强NK细胞的卵巢杀肿瘤功能中的作用。