Mitochondria-targeted Agents in Breast Cancer

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。

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.