Novel Strategy of PDE5-mTOR Inhibition in Attenuation of Cancer Drug Cardiotoxicity

项目摘要 阿霉素(DOX)化疗方案在许多癌症治疗中发挥着重要作用。带长的 癌症长期存活，相当一部分癌症患者仍有早期心血管疾病的风险 DOX化疗的发病率和死亡率。此外，临床研究表明，序贯 用ErbB2抑制剂治疗DOX，曲妥珠单抗在改善癌症控制方面有协同作用 乳腺癌患者的进展和生存，并且比任何一种药物单独使用都要好。然而，这一组合 使用ErbB2抑制剂与DOX联合治疗会导致严重的侵袭性心力衰竭。至 为了克服这一临床问题，我们提出了一种与PDE5抑制剂西地那非(伟哥)联合治疗的新方法。 MTOR抑制剂雷帕霉素预防DOX和DOX严重心脏毒性的序贯治疗 曲妥珠单抗在荷乳腺癌小鼠中的应用。我们将评估西地那非和西地那非的疗效 雷帕霉素对阿霉素诱导的体外心肌细胞死亡和体内心功能的影响。此外，我们还将 通过检测TLR4的表达来确定炎症在心脏毒性发展中的作用。 NLRP3和促炎细胞因子，包括IL-1、β和IL-18。CGMP依赖的蛋白激酶的作用 G(PKG)激活和mTOR抑制及其下游信号通路在抗病毒中的作用 将对DOX引起的心功能障碍进行研究。我们还将研究西地那非和雷帕霉素的作用 曲妥珠单抗增强阿昔洛韦和阿昔洛韦的抗肿瘤作用及改善心脏功能 在临床相关的自发性和正交性乳腺癌小鼠模型中的作用。此外，我们 将确定西地那非和雷帕霉素对心脏特异性ErbB2肥厚的抑制作用 转基因小鼠。由于西地那非和雷帕霉素是临床批准的药物，拟议中的研究可能会有所帮助 正在开发新的联合疗法，用于治疗数以千计的癌症患者 以及全球范围内DOX和曲妥珠单抗的心脏毒性衰弱作用。

Project Summary Doxorubicin (DOX) chemotherapy regimens play a prominent role in many cancer treatments. With long term cancer survivorship, a substantial population of cancer patients remain at risk of early cardiovascular morbidity and mortality due to DOX chemotherapy. Moreover, clinical studies have revealed that sequential treatment of DOX with the ErbB2 inhibitor, Trastuzumab has synergistic effects in improving the control of cancer progression and survival in breast cancer patients, and is better than either drug alone. However, the combination therapies with the ErbB2 inhibitor coupled with DOX cause severe and aggressive form of heart failure. To overcome this clinical problem, we propose a novel combination therapy with PDE5 inhibitor, sildenafil (Viagra) and mTOR inhibitor, rapamycin in preventing the severe cardiotoxicity caused by DOX and DOX with sequential use of Trastuzumab in breast cancer-bearing mice. We will evaluate the therapeutic effect of sildenafil and rapamycin on DOX-induced cardiomyocyte death in vitro and cardiac function in vivo. In addition, we will determine the role of inflammation in the development of cardiotoxicity by measuring the expression of TLR4, NLRP3 and pro-inflammatory cytokines including IL-1β and IL-18. The role of cGMP-dependent protein kinase G (PKG) activation and mTOR inhibition with associated downstream signaling pathways in protecting against DOX-induced cardiac dysfunction will be studied. We will also investigate the effect sildenafil and rapamycin treatment in potentiating the anti-tumor efficacy of DOX and DOX with Trastuzumab and improvement of cardiac function in the clinically relevant mouse models of spontaneous and orthotropic breast cancer. Furthermore, we will determine the effect of sildenafil and rapamycin in attenuation of hypertrophy in cardiac specific ErbB2 transgenic mice. Because sildenafil and rapamycin are clinically approved drugs, the proposed studies may help in developing novel combination therapy for treatment of thousands of cancer patients experiencing the lethal and debilitating cardiotoxic effects of DOX and Trastuzumab worldwide.