Mitochondria-targeted Agents in Breast Cancer

描述（由申请人提供）：我们将开发靶向抗氧化剂（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。我们将使用多柔比星（DOX），一种乳腺癌治疗的一线抗肿瘤药物。DOX引起延迟的剂量依赖性心脏毒性。在临床上，这种副作用是管理与传统的抗氧化剂和铁螯合剂。这一建议为乳腺癌化疗提供了一种新的辅助方法。它的起源是基于以下发现：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）在临床前动物模型和心肌细胞中抑制DOX介导的心脏毒性，和2）MTA（Mito-Q和Mito-CP，一种靶向线粒体的氮氧化物）在乳腺癌细胞中引起抗增殖和细胞毒性作用在转化的乳腺上皮细胞（MCF-7和MDA-MB-231）中，但在非转化的乳腺上皮细胞（MCF-10A）中没有，并且显著增强DOX诱导的乳腺癌细胞毒性。我们推测，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。将在化学诱导的乳腺癌动物模型中使用靶向锝标记的显像剂（99 mTc-Mito 10-MAG 3）监测对化疗的反应。具体而言，我们将：（i）研究单独的MTA和与DOX一起在乳腺癌细胞中的细胞毒性作用，（ii）评估MTA和DOX在过表达多药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，和（iv）评估MTA在DOX处理的心肌细胞和DOX处理的大鼠心肌病模型中的心脏保护和氧自由基清除作用。这些目标将通过使用HPLC-荧光和HPLC-电化学检测技术、血流图和超声心动图来实现。将使用新的物种和目标特异性探针检测活性氧物种的异常生成。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新的方法来提高DOX和其他抗肿瘤药物在乳腺癌治疗中的疗效。 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。这项工作还将使用新型成像技术在动物模型中早期检测乳腺癌。

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.