Targeting Ceramide Glycosylation in AML

靶向 AML 中的神经酰胺糖基化

• 批准号: 8554597
• 负责人: Myles C. Cabot
• 金额: $ 40.31万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554597
• 关键词: Acute Myelocytic Leukemia; Address; Adjuvant; Adult; Apoptosis; Apoptotic; Attenuated; Autophagocytosis; Biochemical; Catabolism; Cell Cycle Arrest; Cell Death; Cell Death Signaling Process; Cell Line; Cell Survival; Cell model; Cells; Ceramides; Clinical; Depressed mood; Disease; Disease remission; Divorce; Drug Metabolic Detoxication; Drug resistance; Enhancers; Equilibrium; Event; Glycolipids; Goals; Instruction; Lipids; Malignant Neoplasms; Metabolism; Multi-Drug Resistance; N-caproylsphingosine; Normal Cell; P-Glycoprotein; P-Glycoproteins; Pathway interactions; Patients; Play; Public Health; Resistance; Role; Signal Transduction; Solubility; Sphingolipids; Sphingomyelins; System; Therapeutic; Tumor Suppressor Proteins; base; cancer cell; chemotherapy; cytotoxic; cytotoxicity; design; effective therapy; experience; glycosylation; in vivo; inhibitor/antagonist; innovation; killings; leukemia; mouse model; nanoliposome; novel; response; trafficking

The sphingolipid ceramide is a potent tumor suppressor that contributes to the promotion of apoptosis and autophagy. Management of these responses in cancer cells is dependent on the dynamic balance between ceramide which is pro-apoptotic and its metabolites, which can promote cell survival. Upregulated glycosylation of ceramide, a major pathway contributing to ceramide detoxification, limits the valuable tumor suppressor effects of ceramide. This proposal will focus on reducing ceramide glycosylation with the goal of devising novel ceramide therapies for treatment of acute myeloid leukemia (AML), the most common type of leukemia in adults. Upregulated ceramide catabolism is associated with multidrug resistance in leukemia. In our study we will use ceramide exogenously in the form of short-chain, cell-permeable C6-ceramide (C6-cer) nanoliposomes, a system that offers advantages over other delivery systems or the use of natural ceramide, which due to solubility and transport limitations, cannot be administered exogenously. Our objective is to develop innovative approaches for treating AML, and this will be achieved by delivering C6-cer in conjunction with adjuvants that will attenuate metabolism and thereby amplify ceramide-driven cell death. To attenuate C6-cer metabolism, we will employ P-glycoprotein (P-gp) antagonists as adjuvants. We hypothesize that intracellular P-gp, because of its role in glycolipid trafficking, will be a highly effective target for attenuating C6-cer metabolism.. We also hypothesize that P-gp antagonists will increase the intracellular levels of both C6-cer and long-chain ceramides and magnify end-point responses (apoptosis, autophagy, cell cycle arrest). Because of the major role that P-gp plays in regulating the metabolism of short-chain ceramides, this project hallmarks a shift in clinical strategy by introducing the use of P-gp antagonists as modulators of ceramide metabolism and enhancers of ceramide cytotoxicity, an activity divorced from the much investigated chemotherapy effluxing/multidrug resistance protein we all know. To make nanoliposomal C6-cer more effective as a therapeutic in AML, the following aims will be pursued: 1) Determine the influence of P-gp expression on C6-cer cytotoxicity and metabolism in AML cell models. Understanding the relationship of P- gp and cellular response to C6-cer is critical for optimizing ceramide-based therapeutics. 2) Determine the effect of inhibiting C6-cer catabolism on cytotoxic response to C6-cer in defined AML cell lines and patient cells. We hypothesize that blocking C6-cer catabolism, including conversion to sphingomyelin, will synergistically amplify cytotoxicity. 3) Elucidate the mechanism of cell death and the signaling events associated with cytotoxicity of combination C6-cer/P-gp antagonists in AML cells. 4) Determine the effect of adjuvant inhibitors on response to C6-cer therapy in in vivo AML mouse models. Dysfunctional ceramide metabolism promotes resistance to apoptosis. We expect to discover that partnering nanoliposomal C6-cer with P-gp antagonists (that block ceramide catabolism) will be a novel, innovative, non-toxic treatment for AML. RELEVANCE (See instructions): Acute myelogenous leukemia (AML), the most common type of leukemia in adults, is an aggressive cancer, and only about 25% of patients who experience remission with chemotherapy remain disease-free. There is thus a pressing need in public health to develop effective therapies that can extend remission and in the best case scenario, offer cure. This project will address this issue by evaluating novel combinations of agents designed to reinforce and potentiate biochemical signals that kill leukemia cells without harm to normal cells.

鞘脂神经酰胺是一种有效的肿瘤抑制剂，有助于促进凋亡和 自噬。癌细胞中这些反应的管理取决于 促凋亡的神经酰胺及其代谢产物，可以促进细胞存活。上调 神经酰胺的糖基化是有助于神经酰胺排毒的主要途径，限制了有价值的肿瘤 神经酰胺的抑制作用。该建议将重点降低神经酰胺糖基化的目的 设计新型神经酰胺治疗急性髓样白血病（AML），这是最常见的类型 成人白血病。神经酰胺的分解代谢与白血病中的多药耐药性有关。在 我们的研究将以短链，可渗透的C6-陶瓷（C6-CER）的形式外源使用神经酰胺 纳米脂质体，该系统比其他输送系统具有优势或使用天然神经酰胺， 由于溶解度和运输局限性，不能外源给予。我们的目标是 开发用于治疗AML的创新方法，这将通过交付C6-Cer结合 佐剂会衰减新陈代谢，从而扩大神经酰胺驱动的细胞死亡。衰减 C6-CER代谢，我们将采用P-糖蛋白（P-GP）拮抗剂作为辅助剂。我们假设这一点 细胞内P-gp由于其在糖脂贩运中的作用，将是衰减的高效目标 C6-CER代谢..我们还假设P-gp拮抗剂将增加两者的细胞内水平 C6-CER和长链神经酰胺，并放大终点反应（凋亡，自噬，细胞周期停滞）。 由于P-gp在调节短链神经酰胺的代谢中起的主要作用，该项目 通过引入P-GP拮抗剂作为神经酰胺的调节剂，标志着临床策略的转变 神经酰胺细胞毒性的新陈代谢和增强子，这种活性与经过深入研究的活性分离 我们都知道的化学疗法排出/多药耐药性蛋白。使纳米脂质体C6-Cer更多 作为AML的治疗性有效，将追求以下目标：1）确定P-gp的影响 AML细胞模型中C6-CER细胞毒性和代谢的表达。了解P-的关系 GP和对C6-CER的细胞反应对于优化基于神经酰胺的治疗剂至关重要。 2）确定 抑制C6-CER分解代谢对定义AML细胞系和患者中C6-CER的细胞毒性反应的影响 细胞。我们假设阻止C6-CER分解代谢，包括转化为鞘磷脂的转化 协同扩增细胞毒性。 3）阐明细胞死亡的机理和信号事件 与AML细胞中C6-CER/P-GP拮抗剂组合的细胞毒性有关。 4）确定 在体内AML小鼠模型中对C6-CER治疗反应的辅助抑制剂。神经酰胺功能失调 代谢促进对凋亡的抗性。我们希望发现与纳米脂质体C6-Cer合作 对于P-GP拮抗剂（该阻滞神经酰胺分解代谢）将是一种新颖的，创新的，无毒的治疗方法 AML。 相关性（请参阅说明）： 急性骨髓性白血病（AML）是成人中最常见的白血病类型，是一种侵略性癌症， 在化疗缓解的患者中，只有大约25％的患者保持无病。有 因此，公共卫生的紧迫需要开发有效的疗法，以扩展缓解并以最佳状态 案例场景，提供治疗。该项目将通过评估代理的新型组合来解决这个问题 旨在增强和增强生化信号，杀死白血病细胞而不会损害正常细胞。