Role of CYP3A4 in Prostate Cancer

CYP3A4 在前列腺癌中的作用

基本信息

批准号：
9169812
负责人：
Vinata B Lokeshwar
金额：
$ 17.99万
依托单位：
AUGUSTA UNIVERSITY
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：
2014-02-11 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9169812
关键词：
4-methylumbelliferone Address Anticoagulants Antineoplastic Agents Apoptosis Apoptotic Area Attenuated Bile fluid Biological Assay Biology CYP3A4 gene Cancer Biology Castration Cells Chemistry Chemosensitization Clinical Country Cytochrome P450 3A4 DNA DU145 Data Dose Down-Regulation Drug Combinations Enzymes Epithelial Cells Family Genetic Polymorphism Goals Growth Health High Pressure Liquid Chromatography Histopathology Human In Vitro Injection of therapeutic agent LNCaP Lead Life Liver Malignant neoplasm of prostate Measures Mediating Messenger RNA Metabolism Metastatic Neoplasm to the Bone Modeling Molecular Mus Neoplasm Metastasis PC3 cell line Pharmaceutical Preparations Prostate Prostatic Neoplasms Proteins Publishing Resistance Role S-Phase Fraction Serum Testing Tissues Toxic effect Transgenic Organisms Translations Treatment Failure Tumor Tissue Variant Xenobiotics Xenograft Model Xenograft procedure abiraterone antitumor effect attenuation base cancer therapy castration resistant prostate cancer choleretic cytotoxic design dietary supplements docetaxel drug metabolism enzyme activity genetic manipulation improved inhibitor/antagonist male neoplastic cell overexpression prevent promoter prostate cancer cell prostate cancer cell line prostate cancer model response screening small molecule tumor

项目摘要

DESCRIPTION (provided by applicant): Castration resistant prostate cancer (CRPC) is incurable as the current anti-CRPC treatments do not extend life beyond a few months. Cytochrome P450 3A4 (3A4) is an enzyme that metabolizes and inactivates a number of xenobiotics, including anti-CRPC drugs Abiraterone and Docetaxel. Although, such metabolism usually occurs in the liver, preliminary data show elevated expression of 3A4 (mRNA and protein) and activity in prostate cancer (PCa) cells, when compared to normal prostate cells. Further, a dietary supplement, 4-methylumbelliferone (MU) downregulates 3A4 expression in PCa cells; consequently MU downregulates 3A4 activity and enhances cytotoxic effects of anti-CRPC drugs. Interestingly, a 3A4-variant (3A41B) generated by DNA polymorphism correlates with PCa metastasis and has high promoter activity. This exploratory project is designed to address an understudied area in PCa biology: is elevated expression of 3A4 in PCa cells a mechanism for their reduced sensitivity to anti-CRPC agents? Further, does downregulation of 3A4 expression in PCa cells, by a non-toxic dietary supplement, enhance the sensitivity of PCa cells to anti- CRPC agents? The role of 3A4 in PCa cells will be examined by determining whether modulation of 3A4 levels (over expression and silencing) and MU treatment alters the sensitivity of PCa cells to anti-CRPC agents. Furthermore, does 3A4 expressed in PCa cells inactivate anti-CRPC drugs and whether MU prevents this inactivation? Studies will also investigate the mechanism by which MU downregulates 3A4 levels; specifically, whether MU increases the degradation of 3A4 mRNA or transcriptionally silences both 3A4 wild type and variant 3A41B promoters. Efficacy of anti-CRPC agents, either alone or in combination with MU will be tested to inhibit the growth and progression of castration-resistant prostate tumors in xenograft models. PCa cells used in the xenograft will be those in which 3A4 expression is either up- or down-regulated. Impact: This exploratory project should reveal the role of 3A4 expressed in PCa cells in modulating the response of PCa cells to anti-CRPC agents. Furthermore, does combination with a non-toxic dietary supplement that specifically targets 3A4 expression enhances the sensitivity of PCa cells to anti-CRPC agents. If successful, the project has potential for clinical translation, in which based on the 3A4 levels in tumors a 3A4 inhibitor could be added to improve response to anti-CRPC treatments.

描述（由申请人提供）：去势抵抗性前列腺癌（CRPC）无法治愈，因为目前的抗 CRPC 治疗不能将生命延长几个月以上。细胞色素 P450 3A4 (3A4) 是一种酶，可代谢和灭活多种异生素，包括抗 CRPC 药物阿比特龙和多西他赛。虽然这种代谢通常发生在肝脏中，但初步数据显示，与正常前列腺细胞相比，前列腺癌 (PCa) 细胞中 3A4（mRNA 和蛋白质）的表达和活性有所升高。此外，膳食补充剂 4-甲基伞形酮 (MU) 可以下调 PCa 细胞中 3A4 的表达；因此，MU 下调 3A4 活性并增强抗 CRPC 药物的细胞毒性作用。有趣的是，由 DNA 多态性产生的 3A4 变体 (3A41B) 与 PCa 转移相关，并且具有高启动子活性。这个探索性项目旨在解决 PCa 生物学中的一个尚未研究的领域：PCa 细胞中 3A4 表达升高是否是其对抗 CRPC 药物敏感性降低的机制？此外，通过无毒膳食补充剂下调 PCa 细胞中 3A4 的表达是否会增强 PCa 细胞对抗 CRPC 药物的敏感性？将通过确定 3A4 水平的调节（过度表达和沉默）和 MU 治疗是否改变 PCa 细胞对抗 CRPC 药物的敏感性来检查 3A4 在 PCa 细胞中的作用。此外，PCa 细胞中表达的 3A4 是否会使抗 CRPC 药物失活，MU 是否会阻止这种失活？研究还将调查 MU 下调 3A4 水平的机制；具体而言，MU 是否会增加 3A4 mRNA 的降解，或在转录上沉默 3A4 野生型和变体 3A41B 启动子。将测试抗CRPC药物单独或与MU组合的功效，以抑制异种移植模型中去势抵抗性前列腺肿瘤的生长和进展。用于异种移植的 PCa 细胞将是 3A4 表达上调或下调的细胞。影响：这个探索性项目应该揭示 PCa 细胞中表达的 3A4 在调节 PCa 细胞对抗 CRPC 药物的反应中的作用。此外，与专门针对 3A4 表达的无毒膳食补充剂组合是否可以增强 PCa 细胞对抗 CRPC 药物的敏感性。如果成功，该项目具有临床转化的潜力，根据肿瘤中的 3A4 水平，可以添加 3A4 抑制剂来改善抗 CRPC 治疗的反应。