Targeting Leukemia Stem Cells with Dietary Selenium

用膳食硒靶向白血病干细胞

• 批准号: 8666541
• 负责人: KUMBLE SANDEEP PRABHU
• 金额: $ 29.41万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 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/8666541
• 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

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.

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）移植表达融合癌蛋白 BCR-ABL 或 MLL-AF9 的造血干细胞（HSC）的 C57BL/6 小鼠的 Sca1+kit+GFP+LSC 作为慢性白血病模型 分别为髓性白血病 (CML) 和 AML，以及 2) M34+Sca1+kit+ LSC，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。