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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

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.

摘要