MARINE NATURAL PRODUCTS AS ANTI-ANGIOGENIC AND ANTI-INVASIVE AGENTS

海洋天然产品作为抗血管生成和抗侵袭剂

• 批准号: 7959461
• 负责人: KHALID A EL SAYED
• 金额: $ 5.51万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959461
• 关键词: Actins; Affinity; Attenuated; Binding; Biomedical Research; Calcitonin; Callyspongia; Cancer Etiology; Cell Polarity; Cell Shape; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Cessation of life; Complex; Computer Assisted; Computer Retrieval of Information on Scientific Projects Database; Development; Epithelium; Funding; Grant; Human; Hydantoins; Institution; Laboratories; Louisiana; Macrolides; Malignant - descriptor; Malignant Squamous Cell Neoplasm; Malignant neoplasm of prostate; Marines; Mediating; Methods; Microfilament Proteins; Modeling; Multi-Drug Resistance; Neoplasm Metastasis; Neuropeptides; P-Glycoprotein; P-Glycoproteins; PC3 cell line; Polymers; Porifera; Prostate; Prostatic Neoplasms; Research; Research Personnel; Resources; Source; Structure-Activity Relationship; Tumorigenicity; United States National Institutes of Health; analog; cancer cell; cytotoxicity; design; latrunculin A; marine natural product; men; monomer; novel; overexpression; pharmacophore; polymerization; receptor; tumor growth

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prostate cancer (PC) is the second leading cause of cancer deaths in men. The neuropeptide calcitonin (CT) and its receptor are exclusively localized in normal prostate epithelium and their expression is deregulated in malignant prostate. Exogenous CT raises tumorigenicity and metastatic potential of several PC cell lines. Disruption of cell-cell adhesion is a key mechanism associated with CT-stimulated prostate tumor growth and metastasis. Actin is a microfilament protein that forms versatile dynamic polymers, which can define cell polarity, control cell shape and promote stable cell-cell and cell-matrix adhesions. Overexpression of ABCB1/P-glycoprotein (P-gp) is one of the most common mechanisms for the development of multidrug resistance (MDR) in cancer cells. Phenylmethylene hydantoins (PMHs) are anti-metastatic leads discovered in our laboratory. PMHs augment cell-cell adhesion complexes, abolish proinvasive actions of CT, and attenuates CT-stimulated tumor growth and metastasis of PCs. The marine-derived macrolide latrunculins A and B are known to reversibly bind actin monomers, disrupting its polymerization. Rationally-designed analogs of latrunculin A were semisynthesized to modulate actin binding affinities and therefore showed potent anti-invasive activity at the nM level without cytotoxicity. Several novel sipholane triterpenoids were isolated from the sponge Callyspongia siphonella and were able to reverse P-gp-mediated multidrug resistance in human epidermoid cancer cells. Computer-assisted modeling methods like CoMFA, CoMSIA, and DISCOtech were used to establish and understand the structure-activity relationship, pharmacophore model, and guide the design of more potent analogs. PMHs, latrunculins, and sipholanes are potential anticancer leads.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 前列腺癌（PC）是男性癌症死亡的第二大原因。神经肽降钙素（CT）及其受体仅位于正常前列腺上皮中，并且它们的表达在恶性前列腺中失调。外源性 CT 会提高多种 PC 细胞系的致瘤性和转移潜力。细胞间粘附的破坏是与 CT 刺激的前列腺肿瘤生长和转移相关的关键机制。肌动蛋白是一种微丝蛋白，可形成多功能动态聚合物，可以定义细胞极性、控制细胞形状并促进稳定的细胞-细胞和细胞-基质粘附。 ABCB1/P-糖蛋白（P-gp）的过度表达是癌细胞产生多药耐药性（MDR）的最常见机制之一。 苯亚甲基乙内酰脲 (PMH) 是我们实验室发现的抗转移先导化合物。 PMH 增强细胞间粘附复合物，消除 CT 的促侵袭作用，并减弱 CT 刺激的肿瘤生长和 PC 转移。已知海洋来源的大环内酯 latrunculins A 和 B 可以可逆地结合肌动蛋白单体，破坏其聚合。合理设计的 latrunculin A 类似物经过半合成来调节肌动蛋白结合亲和力，因此在 nM 水平上表现出有效的抗侵袭活性，且没有细胞毒性。从海绵 Callysponia siphonella 中分离出几种新型西佛烷三萜类化合物，能够逆转人表皮样癌细胞中 P-gp 介导的多药耐药性。使用 CoMFA、CoMSIA 和 DISCOtech 等计算机辅助建模方法来建立和理解构效关系、药效团模型，并指导更有效的类似物的设计。 PMH、latrunculins 和 sipholane 是潜在的抗癌先导化合物。