Mitochondria-targeted Agents in Breast Cancer

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。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。

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.