Targeting Leukemia Stem Cells with Dietary Selenium

用膳食硒靶向白血病干细胞

基本信息

批准号：
8382905
负责人：
KUMBLE SANDEEP PRABHU
金额：
$ 30.32万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8382905
关键词：
9-deoxy-delta-9-prostaglandin D2 Ablation Acute Myelocytic Leukemia Address Affect Agreement Analgesics Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptosis Apoptotic Arachidonic Acids Area Ataxia Binding Biology Blood Bone Marrow C57BL/6 Mouse Cell Line Cell Proliferation Cells Chemopreventive Agent Chronic Myeloid Leukemia Colon Carcinoma Coupled Cyclooxygenase Inhibitors Data Development Diet Dietary Selenium Dinoprostone Disease Disease remission Dose Epidemiology Flow Cytometry Friend leukemia GTP-Binding Proteins Goals Hematopoietic Hematopoietic stem cells Human Immune In Vitro Incidence Individual Indomethacin Infection Inflammatory Intervention Knowledge L-Selenomethionine Leukemic Cell Link MLL-AF9 Malignant Neoplasms Malignant neoplasm of prostate Mediating Metabolism Micronutrients Modeling Molecular Mus Mutate Non-Steroidal Anti-Inflammatory Agents Oncogene Proteins PTGS1 gene Pain management Pathology Pathway interactions Patients Pharmaceutical Preparations Polycythemia Production Proliferating Property Prostaglandin D2 Prostaglandin Receptor Prostaglandin-Endoperoxide Synthase Prostaglandins Publishing Recurrent disease Relapse Retroviridae Rodent Model Role Selenite Selenium Selenocysteine Serum Shunt Device Spleen Splenomegaly Stem cell transplant Supplementation Testing Thromboxane A2 Transplantation Work adult leukemia base bcr-abl Fusion Proteins cancer cell cancer stem cell carbene cyclooxygenase 1 cyclopentenone dietary supplements feeding in vivo inhibitor/antagonist leukemia leukemic stem cell macrophage malignant breast neoplasm methylselenic acid neoplastic cell prevent prostaglandin D receptor prostaglandin R2 D-isomerase receptor selenocyanate selenoprotein self-renewal

项目摘要

DESCRIPTION (provided by applicant): Selenium (Se) is incorporated into selenoproteins as selenocysteine to impart anti-cancer, antioxidant, and anti-inflammatory functions. Based on our ongoing studies, under marginally high Se status, immune cells shunt the arachidonic acid metabolism towards the production of cyclooxygenase (COX)-derived anti-inflammatory cyclopentenone prostaglandin (CyPG) 15d- PGJ2 rather than pro-inflammatory PGE2 and thromboxane A2. Many studies have shown that high Se inhibits the initiation, promotion, and progression in rodent models of breast, colon, and prostate cancer, where apoptosis of bulk cancer cells was enhanced. However, studies are yet to be done to understand the effect of Se on cancer stem cells (CSC), which occupy the apex of the developmental hierarchy with properties of self-renewal, multipotentiality, and strong proliferative capacity. Existing therapie to treat cancer do not eradicate the CSCs and thus, aid in the relapse of many cancers. To fill this pervasive gap, we propose to examine the effect of dietary Se on the proliferation of leukemia stem cells (LSC) in the following three models: 1) transplantation of Sca1+kit+GFP+LSCs from C57BL/6 mice transplanted with hematopoietic stem cells (HSC) that express the fusion oncoproteins BCR-ABL or MLL-AF9 as models of chronic myelogenous leukemia (CML) and AML, respectively, and 2) M34+Sca1+kit+ LSCs from Balb/c mice infected with Friend leukemia retrovirus-polycythemia, a model of acute myelogenous leukemia (AML). Based on the compelling preliminary data that COX inhibitors block the effect of Se-dependent ablation of leukemia in-vivo, we hypothesize that supraphysiological levels of dietary Se increases the production of endogenous CyPGs to specifically target LSCs to apoptosis by activating the p53 pathway. The hypothesis will be tested in three Specific Aims: 1) To examine if high Se supplementation causes the ablation of LSCs; 2) To examine the role of COX pathway metabolites in the selective targeting of LSCs in Se-supplemented mice, and 3) To delineate the mechanism of apoptosis of LSCs by 15d-PGJ2 in Se supplemented mice. Given the epidemiological evidence of lowered serum Se levels in leukemia patients as well as higher incidences of adult leukemia in individuals consuming non-aspirin analgesics, our long- term goal is to understand if Se supplementation of leukemia patients would be beneficial. PUBLIC HEALTH RELEVANCE: The proposal is based on a relatively understudied area in selenium biology that examines the role of this micronutrient in the selective eradication of leukemia stem cells. Under selenium supplemented conditions, the formation of endogenous prostaglandin metabolites and their role in the eradication of leukemia stem cells will be studied using transplantation of leukemia stem cells and ablation of leukemia in three well established murine models.

描述（申请人提供）：硒（Se）作为硒代半胱氨酸掺入硒蛋白中，具有抗癌、抗氧化和抗炎功能。根据我们正在进行的研究，在稍高的 Se 状态下，免疫细胞将花生四烯酸代谢分流为产生环氧合酶 (COX) 衍生的抗炎环戊烯酮前列腺素 (CyPG) 15d- PGJ2，而不是促炎 PGE2 和血栓素 A2。许多研究表明，高硒可以抑制啮齿动物模型中乳腺癌、结肠癌和前列腺癌的发生、促进和进展，从而增强大量癌细胞的凋亡。然而，硒对癌症干细胞（CSC）的影响仍有待研究，癌症干细胞处于发育层次的顶端，具有自我更新、多潜能和强增殖能力的特性。现有的癌症疗法不能根除癌症干细胞，因此会导致许多癌症复发。为了填补这一普遍空白，我们建议在以下三种模型中检查膳食硒对白血病干细胞（LSC）增殖的影响：1）移植造血干细胞移植的 C57BL/6 小鼠的 Sca1+kit+GFP+LSC表达融合癌蛋白 BCR-ABL 或 MLL-AF9 的干细胞 (HSC) 分别作为慢性粒细胞白血病 (CML) 和 AML 模型，以及2) M34+Sca1+kit+ LSCs，来自感染 Friend 白血病逆转录病毒-红细胞增多症（急性髓性白血病 (AML) 模型）的 Balb/c 小鼠。基于令人信服的初步数据，即 COX 抑制剂可阻断体内硒依赖性消融白血病的作用，我们假设饮食中硒的超生理水平会增加内源性 CyPG 的产生，从而通过激活 p53 途径特异性靶向 LSC 使其凋亡。该假设将通过三个具体目标进行检验：1）检查高硒补充是否会导致 LSC 消融； 2) 研究 COX 途径代谢物在补硒小鼠中选择性靶向 LSC 中的作用，以及 3) 阐明 15d-PGJ2 在补硒小鼠中诱导 LSC 凋亡的机制。鉴于白血病患者血清硒水平降低以及服用非阿司匹林镇痛药的个体成人白血病发病率较高的流行病学证据，我们的长期目标是了解白血病患者补充硒是否有益。公共健康相关性：该提案基于硒生物学中相对较少研究的领域，该领域研究了这种微量营养素在选择性根除白血病干细胞中的作用。在补硒条件下，将通过在三个成熟的小鼠模型中移植白血病干细胞和消除白血病来研究内源性前列腺素代谢物的形成及其在根除白血病干细胞中的作用。