Cardioprotective Effect of Phase 3 Clinical Anticancer Agent, RRx-001, in Doxorubicin-Induced Acute Cardiotoxicity in Mice.
Cardioprotective Effect of Phase 3 Clinical Anticancer Agent, RRx-001, in Doxorubicin-Induced Acute Cardiotoxicity in Mice.
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DOI：
10.1021/acs.molpharmaceut.9b00150
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发表时间：
2019-04
影响因子：
4.9
通讯作者：
B. Oronsky;Eilleen S. Y. Ao-ieong;O. Yalcin;C. Carter;P. Cabrales
中科院分区：
文献类型：
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作者：
B. Oronsky;Eilleen S. Y. Ao-ieong;O. Yalcin;C. Carter;P. Cabrales
蒽环类化疗（例如，多柔比星或DOX）与累积的剂量依赖性心脏功能障碍有关，其可导致充血性心力衰竭，这限制了其在临床中的使用和有用性。心脏毒性可在阿霉素治疗结束后急性和/或数月或数年表现出来。实验和人体数据表明，血管紧张素转换酶/血管紧张素受体拮抗剂介导的蒽环类药物毒性的心脏保护作用。在这项研究中，与血管紧张素受体阻滞剂，坎地沙坦，作为阳性对照，我们评估是否预处理与缺氧一氧化氮生成抗癌剂，RRx-001，可以减少急性阿霉素诱导的心脏毒性。将总共24只BALB/c小鼠随机分组，用媒介物、RRx-001、坎地沙坦或无干预对照进行预防性治疗。在三个干预组中的每一个中，小鼠接受DOX治疗。用微导导管进行小鼠压力-容积分析，以表征各组内心血管功能障碍的程度。监测以下血流动力学参数：左心室收缩压（LVSP）、心率和左心室压力最大增加速率（± dp/d tmax）。多柔比星注射后5天，未治疗（使用RRx-001）小鼠显示出显著受损的收缩压（LVSP，-27%; d P/d tmax，-25%;左室发展压（LVDP），+33%; P < 0.05）和总体（每搏输出量（SV），-52%;射血分数（EF），-20%;每搏作功（SW），-62.5%;心率（HR），-18%;心输出量（CO），-57%;平均动脉压（MAP），-30%;全身血管阻力（SVR），+20%; P < 0.05）LV功能。相比之下，RRx-001治疗的小鼠显示出改善的收缩压变量。（LVSP，+27%; d P/d tmax，+25%; LVDP，-33%; P < 0.05）和总体（SV，+52%; EF，+20%; SW，+62.5%; HR，+18%; CO，+57%; MAP，+30%; SVR，-20%; P < 0.05）与未处理的阿霉素小鼠相比的LV功能。与阳性对照坎地沙坦类似，DOX在小鼠中的心脏毒性作用通过预防性施用RRx-001而部分减弱。这些结果表明，RRx-001作为一种多功能抗癌剂，使癌细胞对化疗和放疗的细胞毒性作用敏感，也可能具有有益的心脏保护作用。
Anthracycline chemotherapy (e.g., doxorubicin or DOX) is associated with a cumulative dose-dependent cardiac dysfunction that may lead to congestive heart failure, which limits both its use and usefulness in the clinic. The cardiotoxicity may manifest acutely and/or months or years after treatment with doxorubicin has ended. Experimental and human data have demonstrated that angiotensin-converting enzyme/angiotensin-receptor antagonists mediate a cardioprotective effect against anthracycline toxicity. In this study, with the angiotensin receptor blocker, candesartan, as a positive control, we evaluated whether pretreatment with the hypoxic nitric oxide generating anticancer agent, RRx-001, could reduce acute DOX-induced cardiotoxicity. A total of 24 BALB/c mice were randomized for prophylactic treatment with vehicle, RRx-001, candesartan, or no-intervention control. Within each of the three intervention arms, mice received treatment with DOX. Murine pressure-volume analysis was performed with microconductance catheters to characterize the degree of cardiovascular dysfunction within each group. The following hemodynamic parameters were monitored: left ventricular systolic pressure (LVSP), heart rate, and maximal rate of increase of left ventricular pressure (±d P/d tmax). Five days after doxorubicin injection, untreated (with RRx-001) mice displayed significantly impaired systolic (LVSP, -27%; d P/d tmax, -25%; left ventricular developed pressure (LVDP), +33%; P < 0.05) and global (stroke volume (SV), -52%; ejection fraction (EF), -20%; stroke work (SW), -62.5%; heart rate (HR), -18%; cardiac output (CO), -57%; mean blood arterial pressure (MAP), -30%; systemic vascular resistance (SVR), +20%; P < 0.05) LV functions when compared with the untreated (with RRx-001) group. In contrast, RRx-001-treated mice showed improved variables of systolic (LVSP, +27%; d P/d tmax, +25%; LVDP, -33%; P < 0.05) and global (SV, +52%; EF, +20%; SW, +62.5%; HR, +18%; CO, +57%; MAP, +30%; SVR, -20%; P < 0.05) LV functions compared with untreated doxorubicin mice. Similar to the positive control, candesartan, the cardiotoxic effects of DOX in mice were partially attenuated by the prophylactic administration of RRx-001. These results suggest that RRx-001 as a multifunctional anticancer agent, which sensitizes cancer cells to the cytotoxic effects of chemotherapy and radiation, may also have beneficial cardioprotective effects.