Cruciferous Dithiolethiones for Chronic Heart Failure: Signaling Mechanisms

描述(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种重要的病因。在这种背景下，蒽环类药物阿霉素(Dox)是在多种癌症中具有主要临床活性的最重要的抗癌药物之一。Dox的临床应用受到其累积剂量依赖性心肌病的严重限制，这种心肌病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。铁络合剂Dexrazoxane目前被批准用于预防或减少Dox导致的转移性乳腺癌女性患者的慢性心力衰竭(CHF)。无论是否使用右旋氮杂环己烷和Dox衍生物，在接受Dox治疗的癌症患者中，心力衰竭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在不影响其抗癌活性的情况下预防Dox诱导的CHF。广泛的研究表明，Dox的癌症治疗活性和心脏毒性是通过不同的机制发生的。因此，它很可能开发基于机械的策略，在不影响其抗癌活性的情况下选择性地预防Dox的心脏毒性。我们建议通过长期应用十字花科植物3，2-二硫醇-3-硫酮(D3T)持续协同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，以预防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R15的应用中，我们将研究长期服用D3T对心肌AO/AI酶的持续协同上调是否可以防止或延缓Dox诱导的小鼠心力衰竭的发展，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信号在长期D3T治疗下心脏AO/AI酶持续协同上调中的作用，以及这一信号通路在预防Dox诱导的CHF中的关键作用。最后，我们将确定在B16-F10黑色素瘤肺转移小鼠模型中，这种新的十字花科二硫代硫酮心脏保护方式是否增强了Dox的抗肿瘤活性。鉴于氧化和炎症应激在各种病因的心力衰竭中的关键作用，该项目的成功完成不仅将提供一种新的策略来预防 DOX诱导的CHF，也是干预其他原因引起的CHF的一种有效的CAM方式，如心肌缺血以及其他抗癌药物。在这种背景下，Dox被用作创建CHF的常见化学模型，用于研究分子病理生理学以及心脏保护策略，包括天然产物。

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.