Targeting Ceramide Glycosylation in AML

靶向 AML 中的神经酰胺糖基化

基本信息

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
项目类别：
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

项目摘要

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，有助于促进细胞凋亡和自噬。癌细胞中这些反应的管理取决于之间的动态平衡神经酰胺具有促凋亡作用，其代谢产物可促进细胞存活。上调神经酰胺的糖基化是神经酰胺解毒的主要途径，限制了有价值的肿瘤神经酰胺的抑制作用。该提案将重点关注减少神经酰胺糖基化，目标是设计新的神经酰胺疗法来治疗急性髓性白血病（AML），这是最常见的类型成人白血病。神经酰胺分解代谢上调与白血病的多药耐药性相关。在在我们的研究中，我们将以短链、细胞渗透性 C6-神经酰胺 (C6-cer) 的形式外源使用神经酰胺纳米脂质体，一种比其他递送系统或使用天然神经酰胺具有优势的系统，由于溶解度和运输限制，不能外源给药。我们的目标是开发治疗 AML 的创新方法，这将通过联合提供 C6-cer 来实现佐剂会减弱新陈代谢，从而放大神经酰胺驱动的细胞死亡。减弱 C6-cer代谢，我们将采用P-糖蛋白（P-gp）拮抗剂作为佐剂。我们假设细胞内 P-gp 由于其在糖脂运输中的作用，将成为减弱 C6-cer 代谢。我们还假设 P-gp 拮抗剂会增加细胞内两种物质的水平 C6-cer 和长链神经酰胺并放大终点反应（细胞凋亡、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发挥重要作用，本项目通过引入 P-gp 拮抗剂作为神经酰胺调节剂的使用，标志着临床策略的转变神经酰胺细胞毒性的代谢和增强剂，这种活性与大量研究的结果相分离我们都知道化疗流出/多药耐药蛋白。使纳米脂质体C6-cer更作为 AML 的有效治疗方法，我们将追求以下目标： 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。理解P-的关系 gp 和细胞对 C6-cer 的反应对于优化基于神经酰胺的疗法至关重要。 2）确定抑制 C6-cer 分解代谢对特定 AML 细胞系和患者中 C6-cer 细胞毒性反应的影响细胞。我们假设阻断 C6-cer 分解代谢，包括转化为鞘磷脂，将协同增强细胞毒性。 3）阐明细胞死亡机制和信号事件与 AML 细胞中 C6-cer/P-gp 拮抗剂组合的细胞毒性相关。 4) 确定效果辅助抑制剂对体内 AML 小鼠模型中 C6-cer 治疗反应的影响。功能失调的神经酰胺代谢促进对细胞凋亡的抵抗。我们期望发现合作纳米脂质体 C6-cer 与 P-gp 拮抗剂（阻断神经酰胺分解代谢）一起使用将是一种新颖、创新、无毒的治疗方法反洗钱。相关性（参见说明）：急性髓性白血病 (AML) 是成人最常见的白血病类型，是一种侵袭性癌症，只有约 25% 的化疗缓解患者仍保持无病状态。有因此，公共卫生领域迫切需要开发能够延长缓解期并达到最佳效果的有效疗法。案例场景，提供治疗。该项目将通过评估新的药物组合来解决这个问题旨在增强和增强杀死白血病细胞而不伤害正常细胞的生化信号。