(PQA1) The antipsychotic thioridazine protects against medulloblastoma (MB): volu

(PQA1) 抗精神病药硫利达嗪可预防髓母细胞瘤 (MB)：volu

基本信息

批准号：
8686411
负责人：
LILY Y JAN
金额：
$ 38.62万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686411
关键词：
ABCB1 gene Adverse effects Amines Antipsychotic Agents Apoptosis Astemizole B-Lymphocytes Cardiac Cell Cycle Arrest Cell Cycle Progression Cell Proliferation Cell Survival Cell Volumes Cell membrane Cells Childhood Chloride Ion Clinical Treatment Colon Carcinoma Dopamine Drug usage Endometrial Carcinoma Focal Adhesions G2 Phase Genetic Glioma Growth Heart Block Human In Vitro Intracellular translocation Knock-out Length Lung Neoplasms MAP Kinase Gene MAPK14 gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of cervix uteri Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of prostate Marketing Mental disorders Mitotic Modeling Molecular Mus Neoplasm Metastasis Neuraxis Neuroblastoma Nitrogen P-Glycoprotein PI3K/AKT Pathway interactions Patients Pharmaceutical Preparations Pharmacological Treatment Phenothiazines Physical condensation Positioning Attribute Potassium Channel Psychotic Disorders Psychotropic Drugs Radiosurgery Regulation Renal carcinoma Research Personnel Risk Schizophrenia Signal Transduction Structure Sulfur Surface Testing Tumor Burden Up-Regulation Voltage-Gated Potassium Channel Water Xenograft procedure cancer cell cancer type cell motility channel blockers chemotherapy in vivo large cell Diffuse non-Hodgkin&apos s lymphoma leukemia leukemia/lymphoma lung melanoma malignant breast neoplasm medulloblastoma melanoma migration mouse model novel potassium ion prevent public health relevance small hairpin RNA tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The phenothiazine group of drugs including thioridazine has been widely prescribed for the treatment of psychiatric disorders since the 1940s. The anti-cancer activities of these antipsychotics have intrigued clinicians and researchers since the early 1970s. Whereas thioridazine and several other phenothiazines can block the cardiac hERG voltage-gated potassium channels, they remain on the market because their risk for prolonging the cardiac QTc interval is outweighed by their beneficial effects. The possibility that potassium channel block is one molecular mechanism by which these antipsychotics protect against cancer has never been considered before. We propose to test the original hypothesis that thioridazine protects against medulloblastoma (MB) growth and metastasis by blocking the EAG2 voltage-gated potassium channels that are upregulated in a subset of MBs of human patients, particularly in metastatic MBs. Specifically, we hypothesize that (1) thioridazine block of EAG2 channels prevents MB cell volume reduction for premitotic condensation (PMC) so as to cause cell cycle arrest - those MB cells that venture beyond the G2 phase encounter mitotic catastrophe and perish via apoptosis, and (2) thioridazine block of EAG2 channels reduces water efflux from the trailing edge of migrating MB cells, thereby interfering with MB cell migration by preventing the trailing edge of the cell from shrinking - a local volume regulation essential for cell movement. To test our hypothesis that thioridazine block of EAG2 potassium channels that appear on the surface of mitotic MB cells and on the trailing edge of migrating MB cells to protect against MB growth and metastasis, we will conduct in vitro and in vivo studies to experimentally validate the prediction that the anti-cancer activites of thioridazine can be mimicked by pharmacological treatment with astemizole, a structurally unrelated EAG2 channel blocker. We will further test whether the anti-cancer activities of these two EAG2 channel blockers resemble the effects of reducing EAG2 expression of human MB cells in vitro and in vivo - for mice bearing human MB xenograft, as well as the effects of knocking out Eag2 in mouse MB models. Additional controls will be conducted to confirm that the anti-cancer activities of thioridazine that arise from its block of EAG2 channels are occluded by shRNA knockdown of EAG2 or genetic deletion of Eag2 in mouse models.

描述（由申请人提供）：自 20 世纪 40 年代以来，吩噻嗪类药物（包括硫利达嗪）已被广泛用于治疗精神疾病。自 20 世纪 70 年代初以来，这些抗精神病药物的抗癌活性一直引起临床医生和研究人员的兴趣。尽管硫利达嗪和其他几种吩噻嗪可以阻断心脏 hERG 电压门控钾通道，但它们仍然留在市场上，因为它们延长心脏 QTc 间期的风险超过了它们的有益作用。以前从未考虑过钾通道阻断可能是这些抗精神病药物预防癌症的一种分子机制。我们建议检验最初的假设，即硫利达嗪通过阻断 EAG2 电压门控钾通道来防止髓母细胞瘤 (MB) 生长和转移，该通道在人类患者的一部分 MB 中上调，特别是在转移性 MB 中。具体来说，我们假设 (1) 硫利达嗪阻断 EAG2 通道可防止 MB 细胞因有丝分裂前浓缩 (PMC) 而减少体积，从而导致细胞周期停滞 - 那些冒险超越 G2 期的 MB 细胞会遭遇有丝分裂灾难并通过细胞凋亡而灭亡，并且(2) 硫利达嗪阻断 EAG2 通道，减少迁移 MB 细胞后缘的水流出，从而通过阻止细胞后缘的迁移来干扰 MB 细胞迁移。收缩——细胞运动所必需的局部体积调节。为了检验我们的假设，即硫利达嗪阻断出现在有丝分裂 MB 细胞表面和迁移 MB 细胞后缘的 EAG2 钾通道，以防止 MB 生长和转移，我们将进行体外和体内研究，以实验验证预测甲硫利达嗪的抗癌活性可以通过阿司咪唑（一种结构上不相关的 EAG2 通道阻滞剂）的药物治疗来模拟。我们将进一步测试这两种 EAG2 通道阻滞剂的抗癌活性是否类似于体外和体内降低人 MB 细胞 EAG2 表达的效果（对于携带人 MB 异种移植物的小鼠），以及在小鼠体内敲除 Eag2 的效果。鼠标 MB 型号。我们将进行额外的对照，以确认甲硫利达嗪因阻断 EAG2 通道而产生的抗癌活性会被小鼠模型中 EAG2 的 shRNA 敲低或 Eag2 的基因删除所阻断。