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功效。我们将使用多柔比星（DOX）， 在乳腺癌治疗中的抗肿瘤剂。DOX引起延迟的剂量依赖性心脏毒性。在临床上， 这种副作用可以用常规的抗氧化剂和铁螯合剂来控制。该提案提供了一个新的 乳腺癌化疗的辅助方法。它的起源基于以下发现：1） MTA（例如，Mito-Q是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， 2）MTA（Mito-Q和Mito-CP，一种靶向线粒体的氮氧自由基）引起 在乳腺癌细胞（MCF-7和MDA-MB-231）中的抗增殖和细胞毒性作用，但在非乳腺癌细胞中没有。 转化的乳腺上皮细胞（MCF-10A），并显著增强DOX诱导的乳腺癌细胞 毒性我们假设靶向抗氧化剂能增强DOX介导的抗肿瘤作用。 但减弱DOX心脏毒性。将通过使用 化学诱导乳腺癌中的靶向锝标记显像剂（99 mTc-Mito 10-MAG 3） 肿瘤动物模型。具体地说，我们将：（i）研究单独的MTA和DOX的细胞毒性作用 （ii）评估MTA和DOX在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在体内的辅助化疗效果 乳腺癌模型，和（iv）评估在DOX-1中MTA的心脏保护和氧自由基清除作用。 治疗的心肌细胞和DOX治疗的大鼠心肌病模型。这些目标将会实现 使用HPLC-荧光和HPLC-电化学检测技术， 超声心动图活性氧物质的异常产生将使用新的物质来检测， 目标特异性探针。我们将开发创新的基于MTA的辅助治疗， DOX诱导的心脏毒性。这项研究可能会导致新的方法来改善治疗 DOX和其他抗肿瘤药物在乳腺癌治疗中的疗效。