Role of CYP3A4 in Prostate Cancer

CYP3A4 在前列腺癌中的作用

基本信息

批准号：
8676313
负责人：
Vinata B Lokeshwar
金额：
$ 16.69万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676313
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 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 model public health relevance 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）：由于当前的抗CRPC治疗不会延长生命超过几个月，因此无法治疗cast割前列腺癌（CRPC）。细胞色素P450 3A4（3A4）是一种代谢并使多种异种生物的酶，包括抗CRPC药物阿比里特酮和多西他赛。尽管这种新陈代谢通常发生在肝脏中，但与正常的前列腺细胞相比，前列腺癌（PCA）细胞中3A4（mRNA和蛋白质）和活性的表达升高。此外，饮食补充剂4-甲基固体（MU）在PCA细胞中下调了3A4的表达。因此，MU下调了3A4活性并增强了抗CRPC药物的细胞毒性作用。有趣的是，DNA多态性产生的3A4变化（3A41B）与PCA转移相关，并且具有较高的启动子活性。该探索性项目旨在解决PCA生物学研究研究的研究：PCA细胞中3A4的表达是否升高，是其对抗CRPC剂敏感性降低的机制？此外，通过无毒的饮食补充剂对PCA细胞中3A4表达的下调是否增强了PCA细胞对抗CRPC药物的敏感性？ 3A4在PCA细胞中的作用将通过确定调节3A4水平（表达和沉默）和MU处理是否会改变PCA细胞对抗CRPC药物的敏感性。此外，在PCA细胞中表达的3A4是否会灭活抗CRPC药物，以及MU是否阻止这种失活？研究还将研究MU下调3A4水平的机制；具体而言，MU是增加3A4 mRNA的降解还是转录沉默3A4野生型和变体3A41B启动子。单独或与MU结合使用抗CRPC药物的功效将经过测试，以抑制异种移植模型中抗性耐castration前列腺肿瘤的生长和进展。异种移植中使用的PCA细胞将是3A4表达上调或下调的PCA细胞。影响：该探索性项目应揭示PCA细胞中3A4在调节PCA细胞对抗CRPC药物的响应中的作用。此外，确实与无毒的饮食补充剂结合使用，该补充剂专门针对3A4表达增强了PCA细胞对抗CRPC药物的敏感性。如果成功，该项目具有临床翻译的潜力，其中基于肿瘤中的3A4水平，可以添加3A4抑制剂以改善对抗CRPC治疗的反应。