Mitochondria-targeted Agents in Breast Cancer

乳腺癌中的线粒体靶向药物

• 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
• 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

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 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 增强化疗药物的抗肿瘤效果。我们将使用阿霉素(DOX)，一种前线药物 乳腺癌治疗中的抗肿瘤药物。DOX可引起延迟的剂量依赖性心脏毒性。在临床上， 这种副作用是用传统的抗氧化剂和铁络合剂来控制的。这项建议提供了一个新的 乳腺癌化疗中的辅助途径。它的起源基于以下发现：1) MTAS(例如Mito-Q，一种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)在临床前动物模型中抑制DOX介导的心脏毒性 心肌细胞，以及2)MTA(Mito-Q和Mito-CP，一种针对线粒体的氮氧化物)引起 对乳腺癌细胞(MCF-7和MDA-MB-231)的抗增殖和细胞毒作用，但对非 转化乳腺上皮细胞(MCF-10A)并显著增强阿霉素诱导的乳腺癌细胞 毒性。我们假设线粒体靶向抗氧化剂能增强DOX介导的抗肿瘤作用 但可减轻DOX的心脏毒性。对化疗的反应将使用 线粒体靶向氚标记显像剂(99mTC-Mito10-MAG3)在化学诱导的乳房中的应用 肿瘤动物模型。具体地说，我们将：(I)研究MTA单独和与DOX一起的细胞毒性效应 在乳腺癌细胞中，(Ii)评估MTA和DOX对过表达的乳腺癌细胞的细胞毒作用 多药耐药蛋白，(III)评价MTAS和DOX的体内辅助化疗效果 以及(Iv)评估MTA对DOX-2的心脏保护和清除氧自由基的作用。 处理的心肌细胞和DOX处理的大鼠心肌病模型。这些目标将会实现 利用高效液相-荧光和高效液相-电化学检测技术，对核素扫描和核磁共振成像进行了研究。 超声心动图。使用新的物种将检测到异常产生的活性氧物种-和 特定于目标的探测器。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改善治疗 DOX等抗肿瘤药物在乳腺癌治疗中的疗效。