Ceramides for Breast Cancer Treatment

用于乳腺癌治疗的神经酰胺

• 批准号: 9812698
• 负责人: MARYAM FOROOZESH
• 金额: $ 40.81万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812698
• 关键词: Agreement; American; Animals; Apoptosis; Biological Assay; Breast Cancer Patient; Breast Cancer Treatment; Cancer Patient; Cancer cell line; Cause of Death; Cell Proliferation; Cell Survival; Cells; Ceramidase; Ceramide Signaling Pathway; Ceramide glucosyltransferase; Ceramides; Clinical; Development; Dose; Drug Kinetics; Drug effect disorder; Drug resistance; Effectiveness; Enzymes; Fatty acid glycerol esters; Flavones; Fluorescence; Fluorescence Microscopy; Glucosylceramides; Growth; Histology; Human; Immunochemistry; In Vitro; Induction of Apoptosis; Injections; MCF7 cell; Malignant Neoplasms; Mammary gland; Metastatic breast cancer; Methods; Multi-Drug Resistance; Neoplasm Metastasis; Nude Mice; P-Glycoprotein; P-Glycoproteins; Participant; Pathogenesis; Pathway interactions; Patients; Play; Procedures; Process; Publishing; Quality of life; Rattus; Research Training; Resistance; Role; Series; Signal Pathway; Sphingolipids; Structure; Students; Survival Rate; System; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Toxicology; Training Programs; Treatment Failure; Woman; analog; anti-cancer; anticancer activity; base; cancer cell; cancer therapy; chemotherapeutic agent; clinical candidate; fluorophore; improved; in vivo; malignant breast neoplasm; migration; mortality; novel; novel therapeutics; response; senescence; small molecule; tool; tumor; undergraduate research

PROJECT SUMMARY/ABSTRACT Many studies have shown a correlation between the sphingolipid signaling pathway and cancer pathogenesis as well as drug-resistance. The central molecule in sphingolipid pathway, ceramide, is involved in the induction of apoptosis, senescence, and growth arrest in many human cancers including breast cancer. Recent studies have shown that certain ceramide analogs possess the capability of preferentially killing resistant cancer cells and/or inhibiting glucosylceramide synthase (GCS) activity, which is highly correlated to cancer multidrug-resistance. The main hypothesis of this project is that ceramide analogs can be developed as new therapeutic agents for the treatment of chemo-resistant and aggressive metastatic breast cancers influencing clinical cancer treatment concepts. Our Secondary hypothesis is that self-fluorescent ceramide analogs can be used to affirm known ceramide mechanisms of action, determine potential new mechanisms of action, and discover novel targets and interactions. Four specific aims are proposed for the Project: Specific Aim 1 - Development of highly potent selective agents for killing resistant cancer cells as candidates for clinical treatment of breast cancer multidrug-resistance and metastasis; Specific Aim 2 - Determination of the mechanistic factors leading to the apoptosis of resistant and metastatic cells, and investigating the relationship between preferential killing of resistant cancer cells and glucosylceramide synthase (GCS) and ceramidase inhibition by ceramide analogs; Specific Aim 3 - Using a novel experimental tool, self-fluorescent small molecules, for investigating the distribution and action of ceramides in cancer cells; and Specific Aim 4 - Determination of the in vivo effects of the most potent target ceramide analog(s). To achieve the Specific Aim 1, 40-45 self-fluorescent ceramide analogs will be synthesized with extended aromatic conjugated systems. To achieve the Specific Aim 2, general anticancer activity screenings will be performed to identify the effective and selective ceramide analogs. A series of mechanistic studies on the potent ceramide analogs will be performed to examine whether the analogs induce apoptosis, and if yes, through which pathway(s). A glucosylceramide level assay, GCS and P-gp level assays, resistance-reversal assays, and ceramidase inhibition assays will determine the effects of the target analogs on the activity and expression of GCS and P-gp and ceramidase. To achieve the Specific Aim 3, through fluorescence microscopy, distribution and actions of the target fluorescent ceramide analogs will be tracked in treated cells, validating the mechanisms of action. Finally, most potent analogs will be used in animal studies to achieve the Specific Aim 4. The long-term objective of this project is to improve the survival rate and quality of life of breast cancer patients by targeting the ceramide signaling pathway. Undergraduate research students, including participants in research training programs, will be involved in all aspects of the Project.

项目总结/摘要 许多研究表明鞘脂信号通路与癌症之间存在相关性 发病机制以及耐药性。鞘脂途径中的中心分子神经酰胺也参与其中 在包括乳腺癌在内的许多人类癌症中诱导细胞凋亡、衰老和生长停滞。 最近的研究表明，某些神经酰胺类似物具有优先杀死 耐药癌细胞和/或抑制葡糖神经酰胺合酶（GCS）活性，其与 癌症多药耐药性。该项目的主要假设是可以开发神经酰胺类似物 作为治疗化学抗性和侵袭性转移性乳腺癌的新治疗剂 影响临床癌症治疗的概念。我们的次要假设是，自荧光神经酰胺 类似物可用于确认已知的神经酰胺作用机制，确定潜在的新机制， 行动，并发现新的目标和相互作用。 该项目提出了四个具体目标： 具体目标1 -开发用于杀死耐药癌细胞的高效选择性试剂作为候选物 用于临床治疗乳腺癌多药耐药和转移; 具体目标2 -确定导致耐药和转移性肿瘤细胞凋亡的机制因素 细胞，并研究优先杀死耐药癌细胞和 葡糖神经酰胺合酶（GCS）和神经酰胺类似物对神经酰胺酶的抑制; 具体目标3 -使用一种新的实验工具，自荧光小分子，研究 神经酰胺在癌细胞中的分布和作用;以及 具体目的4 -测定最有效的靶神经酰胺类似物的体内作用。 为了实现具体目标1，将合成40-45种自荧光神经酰胺类似物， 延伸芳香共轭体系。为了实现具体目标2，一般抗癌活性筛选 以鉴定有效的和选择性的神经酰胺类似物。一系列的机理研究， 将进行有效的神经酰胺类似物以检查类似物是否诱导细胞凋亡，如果是， 通过何种途径（S）。葡萄糖神经酰胺水平测定、GCS和P-gp水平测定、耐药逆转 测定和神经酰胺酶抑制测定将确定靶类似物对活性的影响， GCS、P-gp和神经酰胺酶的表达。为了实现具体目标3，通过荧光 将在处理的细胞中跟踪目标荧光神经酰胺类似物的显微镜、分布和作用， 验证行动机制。最后，大多数有效的类似物将用于动物研究，以实现 具体目标4。 本项目的长期目标是提高乳腺癌的生存率和生活质量 癌症患者通过靶向神经酰胺信号通路。本科研究生，包括 研究培训计划的参与者将参与该项目的各个方面。