ANTILEUKEMIA ACTIVITY OF PERILLYL ALCOHOL

紫苏醇的抗白血病活性

• 批准号: 6052013
• 负责人: STEVEN S CLARK
• 金额: $ 15.8万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6052013
• 关键词: antileukemic agent; antineoplastics; apoptosis; biological signal transduction; cell cycle; chromosome translocation; chronic myelogenous leukemia; disease /disorder model; drug screening /evaluation; enzyme activity; enzyme inhibitors; gene expression; interleukin 3; laboratory mouse; mitogen activated protein kinase; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplastic transformation; nonhuman therapy evaluation; oncogenes; pharmacokinetics; protein tyrosine kinase; protooncogene

The Bcr/Abl oncogene encodes a tyrosine kinase that is expressed in leukemias that carry the Philadelphia chromosome translocation (Ph+). The kinase interacts with different cell signaling pathways to cause factor-independent growth, resistance to apoptosis and oncogenic transformation. These pleiotropic activities of Bcr/Abl affect the pathogenesis of Ph+ leukemias by inhibiting the normal rate of cell death and by enabling Ph+ cells to resist conventional chemotherapy that induces apoptosis in other leukemias. A central hypothesis of this proposal is that inhibition of signaling pathways downstream of the Bcr/Abl kinase should render leukemia cells dependent on growth factors and sensitive to apoptosis. Perillyl alcohol (POH) belongs to a new family of chemotherapy agents and has shown excellent therapeutic rations in rodent carcinoma models. The range of potential anti-tumor activities of POH overlaps with some signaling pathways that are affected by the Bcr/Abl kinase. Thus, POH is a logical compound to test for anti- leukemia activity in Bcr/Abl-induced leukemia. Preliminary experiments demonstrated that in Bcr/Abl-transformed cells, POH rapidly induced G1 arrest and apoptosis. In contrast, Bcr/Abl- transformed cells were resistant to apoptosis induced by different conventional chemotherapy agents. This anti-leukemia activity of POH closely correlated with inhibition of the Raf-ERK signaling pathway downstream of Bcl/Abl. On the other hand, POH treatment did not affect other Bcr/Abl signals that are responsible for maintaining expression of c- Myc. Normally, expression of c-Myc is cell cycle regulated, however, when c-Myc expression is enforced during G1 arrest, cells undergo apoptosis. Therefore, POH may uncouple a Bcr/Abl signaling pathway through Raf that is necessary for maintaining cell growth, while not affecting other Bcr/Abl signals that induce constitutive c-Myc expression. This combination may lead to apoptosis in leukemia cells. This model will be evaluated further by examining 1) the role of the Bcr/Abl oncogene in sensitizing cells to POH, 2) how POH affects signaling through Raf, and 3) whether POH induces Myc-dependent apoptosis in leukemia cells.

Bcr/Abl 癌基因编码一种酪氨酸激酶，该酪氨酸激酶在携带费城染色体易位 (Ph+) 的白血病中表达。该激酶与不同的细胞信号传导途径相互作用，导致不依赖因子的生长、抗凋亡和致癌转化。 Bcr/Abl 的这些多效性活性通过抑制正常的细胞死亡率以及使 Ph+ 细胞能够抵抗诱导其他白血病细胞凋亡的常规化疗来影响 Ph+ 白血病的发病机制。该提议的一个中心假设是，抑制 Bcr/Abl 激酶下游的信号通路会使白血病细胞依赖于生长因子并对细胞凋亡敏感。紫苏醇（POH）属于新的化疗药物家族，在啮齿动物癌症模型中表现出优异的治疗效果。 POH 的潜在抗肿瘤活性范围与受 Bcr/Abl 激酶影响的一些信号通路重叠。因此，POH 是测试 Bcr/Abl 诱导的白血病中的抗白血病活性的合理化合物。初步实验表明，在Bcr/Abl转化细胞中，POH迅速诱导G1期阻滞和细胞凋亡。相反，Bcr/Abl转化细胞对不同常规化疗药物诱导的细胞凋亡具有抵抗力。 POH 的这种抗白血病活性与 Bcl/Abl 下游 Raf-ERK 信号通路的抑制密切相关。另一方面，POH处理不影响负责维持c-Myc表达的其他Bcr/Abl信号。通常，c-Myc 的表达受细胞周期调节，但是，当在 G1 停滞期间强制执行 c-Myc 表达时，细胞会发生凋亡。因此，POH 可能通过 Raf 解偶联维持细胞生长所必需的 Bcr/Abl 信号通路，同时不影响诱导组成型 c-Myc 表达的其他 Bcr/Abl 信号。这种组合可能导致白血病细胞凋亡。该模型将通过检查 1) Bcr/Abl 癌基因在使细胞对 POH 敏感中的作用、2) POH 如何影响通过 Raf 的信号传导以及 3) POH 是否诱导白血病细胞中 Myc 依赖性细胞凋亡来进一步评估。