Mitochondria-targeted Agents in Breast Cancer

乳腺癌中的线粒体靶向药物

基本信息

批准号：
8271285
负责人：
BALARAMAN KALYANARAMAN
金额：
$ 30.59万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-14 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8271285
关键词：
ABCB1 gene Acetylcysteine Adenoviruses Adjuvant Adjuvant Chemotherapy Adjuvant Therapy Adult Adverse effects Animal Model Anthracenes Anthracyclines Antibiotics Antioxidants Apoptosis Attenuated Biological Assay Breast Breast Cancer Cell Breast Cancer Early Detection Breast Cancer Model Breast Cancer Treatment Breast Carcinoma Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cardiovascular Diseases Cations Cell Proliferation Cell Survival Cells Chelating Agents Chemotherapy-Oncologic Procedure Clinical Coupled DNA Fragmentation Detection Dose Doxorubicin Echocardiography Enzymes Epithelial Cells Fluorescence Gene Transfer Generations Glycogen Branching Enzyme Goals High Pressure Liquid Chromatography Hodgkin Disease Image Imaging Techniques Iron Label Lead Link MCF7 cell Mammary Neoplasms Mammary gland Measures Mediating Methylnitrosourea Mitochondria Modeling Monitor Multi-Drug Resistance Myocardial Myocardium Neurodegenerative Disorders Non-Malignant Organ Oxidative Stress P-Glycoprotein Patients Pharmaceutical Preparations Proteins Quinones Rattus Reactive Oxygen Species Reporting Research Respiratory Chain Technetium Techniques Testing Thymidine Toxic effect Treatment Efficacy Ubiquinone Up-Regulation Vitamin E Western Blotting Work analog antioxidant therapy antitumor agent base chemotherapeutic agent chemotherapy clinically relevant combat cyclooxygenase 2 cytotoxic cytotoxicity dimethylbenzanthracene duramycin imaging modality imaging probe improved in vivo innovation leukemia malignant breast neoplasm mimetics novel overexpression pre-clinical research study response success tempol tumor tumor growth uptake

ABCB1 gene Acetylcysteine Adenoviruses Adjuvant Adjuvant Chemotherapy Adjuvant Therapy Adult Adverse effects Animal Model Anthracenes Anthracyclines Antibiotics Antioxidants Apoptosis Attenuated Biological Assay Breast Breast Cancer Cell Breast Cancer Early Detection Breast Cancer Model Breast Cancer Treatment Breast Carcinoma Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cardiovascular Diseases Cations Cell Proliferation Cell Survival Cells Chelating Agents Chemotherapy-Oncologic Procedure Clinical Coupled DNA Fragmentation Detection Dose Doxorubicin Echocardiography Enzymes Epithelial Cells Fluorescence Gene Transfer Generations Glycogen Branching Enzyme Goals High Pressure Liquid Chromatography Hodgkin Disease Image Imaging Techniques Iron Label Lead Link MCF7 cell Mammary Neoplasms Mammary gland Measures Mediating Methylnitrosourea Mitochondria Modeling Monitor Multi-Drug Resistance Myocardial Myocardium Neurodegenerative Disorders Non-Malignant Organ Oxidative Stress P-Glycoprotein Patients Pharmaceutical Preparations Proteins Quinones Rattus Reactive Oxygen Species Reporting Research Respiratory Chain Technetium Techniques Testing Thymidine Toxic effect Treatment Efficacy Ubiquinone Up-Regulation Vitamin E Western Blotting Work analog antioxidant therapy antitumor agent base chemotherapeutic agent chemotherapy clinically relevant combat cyclooxygenase 2 cytotoxic cytotoxicity dimethylbenzanthracene duramycin imaging modality imaging probe improved in vivo innovation leukemia malignant breast neoplasm mimetics novel overexpression pre-clinical research study response success tempol tumor tumor growth uptake

展开

项目摘要

ABSTRACT We will develop mitochondria-targeted antioxidants (MTAs) and imaging probes that will mitigate cardiotoxicity and enhance antitumor efficacies of chemotherapeutic drugs. We will use doxorubicin (DOX), a front-line antitumor agent in breast cancer treatment. DOX causes delayed dose-dependent cardiotoxicity. Clinically, this side effect is managed with conventional antioxidants and iron chelators. This proposal provides a new adjuvant approach in breast cancer chemotherapy. Its genesis is based upon the following discoveries: 1) MTAs (e.g., Mito-Q, a synthetic drug analog of an endogenous antioxidant, Co-enzyme-Q, present in the mitochondrial respiratory chain) inhibit DOX-mediated cardiotoxicity in a preclinical animal model and in cardiomyocytes, and 2) MTAs (Mito-Q and Mito-CP, a nitroxide targeted to mitochondria) cause antiproliferative and cytotoxic effects in breast cancer cells (MCF-7 and MDA-MB-231) but not in non- transformed breast epithelial cells (MCF-10A) and significantly enhance DOX-induced breast cancer cell toxicity. We hypothesize that mitochondria-targeted antioxidants enhance DOX-mediated antitumor effects but attenuate DOX cardiotoxicity. Response to chemotherapy will be monitored by using the mitochondria-targeted technetium-labeled imaging agents (99mTc-Mito10-MAG3) in a chemically-induced breast carcinoma animal model. Specifically, we will: (i) Investigate the cytotoxic effects of MTAs alone and with DOX in breast cancer cells, (ii) Assess the cytotoxic effects of MTAs and DOX in breast cancer cells overexpressing multi-drug resistant protein, (iii) Evaluate the adjuvant chemotherapeutic effects of MTAs and DOX in an in vivo breast cancer model, and (iv) Assess the cardioprotective and oxy-radical scavenging effects of MTAs in DOX- treated cardiomyocytes and in DOX-treated rat cardiomyopathy model. These aims will be accomplished using HPLC-fluorescence and HPLC-electrochemical detection techniques, scintimammography and echocardiography. Abnormal generation of reactive oxygen species will be detected using novel species- and target-specific probes. We will develop innovative MTA-based adjuvant therapy that can be used to inhibit DOX-induced cardiotoxicity. This research may potentially lead to novel ways for improving the therapeutic efficacy of DOX and other antitumor agents used in breast cancer treatment.

抽象的我们将开发靶向线粒体的抗氧化剂（MTA）和成像探针，以减轻心脏毒性并增强化学治疗药物的抗肿瘤功效。我们将使用前线阿霉素（dox）乳腺癌治疗中的抗肿瘤剂。 DOX导致剂量依赖性心脏毒性延迟。临床上该副作用由常规的抗氧化剂和铁螯合剂来管理。该建议提供了一个新的乳腺癌化疗中的辅助方法。它的起源基于以下发现：1） MTA（例如Mito-Q，一种内源性抗氧化剂的合成药物类似物，共酶-Q，存在于线粒体呼吸链）在临床前动物模型中抑制DOX介导的心脏毒性心肌细胞和2）MTA（MITO-Q和MITO-CP，靶向线粒体的氮氧化物）导致乳腺癌细胞中的抗增生性和细胞毒性作用（MCF-7和MDA-MB-231），但在非 - 转化的乳房上皮细胞（MCF-10A），并显着增强了DOX诱导的乳腺癌细胞毒性。我们假设线粒体靶向抗氧化剂可增强DOX介导的抗肿瘤影响，但减弱了DOX心脏毒性。对化学疗法的反应将通过使用在化学诱导的乳房中，线粒体靶向的Technetium标签成像剂（99mtc-Mito10-MAG3）癌动物模型。具体而言，我们将：（i）单独研究MTA和DOX的细胞毒性作用在乳腺癌细胞中，（ii）评估MTA和DOX在过表达的乳腺癌细胞中的细胞毒性作用多药耐药蛋白（III）评估MTA和DOX在体内的辅助化学治疗作用乳腺癌模型，（iv）评估MTA在DOX- 经过治疗的心肌细胞和DOX处理的大鼠心肌病模型。这些目标将实现使用HPLC荧光和HPLC电子化学检测技术，闪烁肌摄影和超声心动图。使用新型物种和目标特异性探针。我们将开发创新的基于MTA的辅助治疗，可用于抑制 DOX诱导的心脏毒性。这项研究可能会导致改善治疗的新方法在乳腺癌治疗中使用的DOX和其他抗肿瘤药的功效。