Cruciferous Dithiolethiones for Chronic Heart Failure: Signaling Mechanisms

描述（由申请人提供）：慢性心力衰竭是主要的心血管疾病负担。虽然冠心病是慢性心力衰竭的主要原因，但药物治疗，特别是抗癌药物已日益成为一个重要的病因。在这种背景下，蒽环类药物阿霉素（Dox）是最重要的抗癌药物之一，在多种癌症中具有重要的临床活性。Dox的临床应用在一定程度上受到其累积剂量依赖性心肌病的限制，这被认为是通过氧化还原金属离子/自由基介导的机制发生的。铁螯合剂dexrazoxane目前被批准用于预防或减少dox诱导的转移性乳腺癌女性慢性心力衰竭（CHF）。无论使用右razoxane还是Dox衍生物，在接受Dox治疗的癌症患者中，CHF的发展仍然是一个关键的临床问题。因此，迫切需要开发更有效的策略来预防dox诱导的CHF，同时不影响其抗癌活性。广泛的研究表明，Dox的癌症治疗活性及其心脏毒性通过不同的机制发生。因此，有可能开发基于机械的策略来选择性地防止Dox心脏毒性而不损害其抗癌活性。我们建议通过长期使用十字花科3H- 1,2-二硫基-3-硫酮（D3T）治疗，持续协调上调心肌中广泛的抗氧化/抗炎（AO/AI）酶，作为一种高效的CAM策略，以保护dox诱导的CHF并增强其抗肿瘤活性，从而提高这种广泛使用的抗癌药物的治疗效果。为此，在本R15应用中，我们将研究长期给药D3T对心肌AO/AI酶的持续协调上调是否能阻止或延缓Dox诱导的CHF的发展，该模型与Dox治疗的癌症患者的情况非常相似。我们还将研究Nrf2信号通路在长期D3T治疗心脏AO/AI酶持续协调上调中的作用，以及该信号通路在预防dox诱导的CHF中的关键作用。最后，我们将在B16-F10黑色素瘤肺转移小鼠模型中确定这种基于十字花科二硫代硫肽的新型心脏保护模式是否增强了Dox的抗肿瘤活性。鉴于氧化应激和炎症应激在各种病因性心力衰竭中的重要作用，本项目的成功完成不仅将为预防和治疗心力衰竭提供一种新的策略

DESCRIPTION (provided by applicant): Chronic heart failure is a major cardiovascular disease burden. Although coronary heart disease is the chief cause of chronic heart failure, drug therapies, especially anticancer drugs have been increasingly becoming a significant etiology. In this context, the anthracycline agent, doxorubicin (Dox) is one of the most important anticancer drugs with major clinical activity in a wide variety of cancers. The clinical use of Dox is severel limited by its cumulative dose-dependent cardiomyopathy, which is believed to occur via redox metal ion/free radical-mediated mechanisms. The iron-chelating agent, dexrazoxane is currently approved to prevent or reduce Dox-induced chronic heart failure (CHF) in women with metastatic breast cancer. Regardless of the use of dexrazoxane as well as Dox derivates, development of CHF remains a critical clinical problem in cancer patients treated with Dox. Hence, there is an urgent need to develop more effective strategies to protect against Dox-induced CHF without compromising its anticancer activity. Extensive studies show that the cancer therapeutic activity of Dox and its cardiotoxicity occur via distinct mechanisms. Therefore, it is likely to develop mechanistically-based strategies to selectively protect against Dox cardiotoxicity without compromising its anticancer activity. We propose the sustained coordinated upregulation of a wide spectrum of antioxidative/anti-inflammatory (AO/AI) enzymes in myocardium by long-term treatment with cruciferous 3H- 1,2-dithiole-3-thione (D3T) as a highly effective CAM strategy for protecting against Dox-induced CHF and potentiating its antitumor activity, and thereby enhancing the therapeutic efficacy of this widely used anticancer drug. To this end, in this R15 application we will investigate if the sustained coordinated upregulation of myocardial AO/AI enzymes by long-term D3T administration prevents or retards the development of Dox- induced CHF in a mouse model that closely mimics the situations in Dox-treated cancer patients. We will also investigate the role of Nrf2 signaling in the sustained coordinated upregulation of cardiac AO/AI enzymes by long-term treatment with D3T as well as the critical involvement of this signaling pathway in protecting against Dox-induced CHF. Finally, we will determine if this novel cruciferous dithiolethione-based cardioprotective modality potentiates Dox's antitumor activity in a mouse model of B16-F10 melanoma lung metastasis. In view of the crucial role of oxidative and inflammatory stress in heart failure of various etiologie, successful completion of this project will provide not only a novel strategy for protecting against Dox-induced CHF, but also an effective CAM modality for the intervention of CHF resulting from other causes, such as myocardial ischemia as well as other anticancer drugs. In this context, Dox is used as a common chemical model to create CHF for studying the molecular pathophysiology as well as cardioprotective strategies, including natural products.