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：
8089425
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/8089425
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 public health relevance research study response success tempol tumor tumor growth uptake

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The proposed research is clinically relevant in that results obtained from this work will likely mitigate the adverse side effects associated with breast cancer chemotherapy. This work will also enable early detection of breast cancer in an animal model using a novel imaging technique.

描述（由申请人提供）：我们将开发线粒体靶向抗氧化剂（MTA）和成像探针，以减轻心脏毒性并增强化疗药物的抗肿瘤功效。我们将使用阿霉素（DOX），一种乳腺癌治疗的一线抗肿瘤药物。 DOX 会引起延迟的剂量依赖性心脏毒性。临床上，这种副作用可以通过传统的抗氧化剂和铁螯合剂来控制。该提案为乳腺癌化疗提供了一种新的辅助方法。其起源基于以下发现：1) MTA（例如 Mito-Q，内源性抗氧化剂辅酶-Q 的合成药物类似物，存在于线粒体呼吸链中）可抑制临床前动物中 DOX 介导的心脏毒性模型和心肌细胞中，2) MTA（Mito-Q 和 Mito-CP，一种针对线粒体的氮氧化合物）在乳腺癌细胞中引起抗增殖和细胞毒性作用(MCF-7 和 MDA-MB-231)，但不在未转化的乳腺上皮细胞 (MCF-10A) 中，并且显着增强 DOX 诱导的乳腺癌细胞毒性。我们假设线粒体靶向抗氧化剂增强 DOX 介导的抗肿瘤作用，但减弱 DOX 的心脏毒性。将通过在化学诱导的乳腺癌动物模型中使用线粒体靶向锝标记成像剂 (99mTc-Mito10-MAG3) 来监测对化疗的反应。具体来说，我们将：（i）研究单独使用 MTA 以及与 DOX 联合使用对乳腺癌细胞的细胞毒性作用，（ii）评估 MTA 和 DOX 在过度表达多重耐药蛋白的乳腺癌细胞中的细胞毒性作用，（iii）评估MTA 和 DOX 在体内乳腺癌模型中的辅助化疗作用，以及 (iv) 评估心脏保护和氧自由基清除作用DOX 处理的心肌细胞和 DOX 处理的大鼠心肌病模型中 MTA 的变化。这些目标将通过高效液相色谱荧光和高效液相电化学检测技术、闪烁X线摄影和超声心动图来实现。将使用新型物种和目标特异性探针来检测活性氧的异常产生。我们将开发基于 MTA 的创新辅助疗法，可用于抑制 DOX 引起的心脏毒性。这项研究可能会带来新的方法来提高 DOX 和其他用于乳腺癌治疗的抗肿瘤药物的治疗效果。公共卫生相关性：拟议的研究具有临床相关性，因为从这项工作中获得的结果可能会减轻与乳腺癌化疗相关的不良副作用。这项工作还将利用新型成像技术在动物模型中早期检测乳腺癌。