Aldose reductase inhibitor, fidarestat prevents doxorubicin-induced endothelial cell death and dysfunction.
Aldose reductase inhibitor, fidarestat prevents doxorubicin-induced endothelial cell death and dysfunction.
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DOI：
10.1016/j.bcp.2018.02.018
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发表时间：
2018-04
影响因子：
5.8
通讯作者：
Ramana KV
中科院分区：
文献类型：
--
作者：
Sonowal H;Pal P;Shukla K;Saxena A;Srivastava SK;Ramana KV
尽管阿霉素（Dox）是乳腺癌、血癌和肺癌最广泛使用的化疗药物之一，但它在结肠癌中的使用受到限制，因为高剂量使用会增加耐药性和严重的心脏毒性副作用，从而增加死亡率。因此，需要更好的辅助治疗，以提高化疗疗效，减少心脏毒性。我们最近发现醛糖还原酶抑制剂非达司他增加dox诱导的结肠癌细胞死亡并减少心肌病。然而，非达司他在预防dox诱导的内皮功能障碍（一种对心血管并发症至关重要的病理事件）中的功效尚不清楚。在这里，我们在体外和体内研究了非达司他对dox诱导的内皮细胞毒性和功能障碍的影响。Dox与人脐静脉内皮细胞（HUVECs）孵育显著增加内皮细胞死亡，而非达司他预处理可防止内皮细胞死亡。此外，非达司他还能阻止dox诱导的HUVECs氧化应激、活性氧（ROS）的形成和Caspase-3的激活。非达司他还能阻止dox诱导的单核细胞粘附HUVECs和ICAM-1和VCAM-1的表达。非达司他预处理HUVECs恢复了dox诱导的一氧化氮（NO）水平和eNOS表达的下降。用Dox处理HUVECs引起NF-κB的激活和各种炎症细胞因子和趋化因子的表达显著增加，这是非达司他预处理可以阻止的。最重要的是，非达司他可以阻止dox诱导的小鼠心肌细胞肥大和主动脉组织中eNOS、iNOS和3-硝基酪氨酸的表达。此外，非达司他在体内减弱了dox诱导的各种炎症细胞因子和趋化因子的表达。因此，我们的研究结果表明，通过防止dox诱导的内皮细胞毒性和功能障碍，AR抑制剂可以避免与蒽环类药物化疗相关的心脏毒性。
Despite doxorubicin (Dox) being one of the most widely used chemotherapy agents for breast, blood and lung cancers, its use in colon cancer is limited due to increased drug resistance and severe cardiotoxic side effects that increase mortality associated with its use at high doses. Therefore, better adjuvant therapies are warranted to improve the chemotherapeutic efficacy and to decrease cardiotoxicity. We have recently shown that aldose reductase inhibitor, fidarestat, increases the Dox-induced colon cancer cell death and reduces cardiomyopathy. However, the efficacy of fidarestat in the prevention of Dox-induced endothelial dysfunction, a pathological event critical to cardiovascular complications, is not known. Here, we have examined the effect of fidarestat on Dox-induced endothelial cell toxicity and dysfunction in vitro and in vivo. Incubation of human umbilical vein endothelial cells (HUVECs) with Dox significantly increased the endothelial cell death, and pre-treatment of fidarestat prevented it. Further, fidarestat prevented the Dox-induced oxidative stress, formation of reactive oxygen species (ROS) and activation of Caspase-3 in HUVECs. Fidarestat also prevented Dox-induced monocyte adhesion to HUVECs and expression of ICAM-1 and VCAM-1. Fidarestat pretreatment to HUVECs restored the Dox-induced decrease in the Nitric Oxide (NO)-levels and eNOS expression. Treatment of HUVECs with Dox caused a significant increase in the activation of NF-κB and expression of various inflammatory cytokines and chemokines which were prevented by fidarestat pre-treatment. Most importantly, fidarestat prevented the Dox-induced mouse cardiac cell hypertrophy and expression of eNOS, iNOS, and 3-Nitrotyrosine in the aorta tissues. Further, fidarestat blunted the Dox-induced expression of various inflammatory cytokines and chemokines in vivo. Thus, our results suggest that by preventing Dox-induced endothelial cytotoxicity and dysfunction, AR inhibitors could avert cardiotoxicity associated with anthracycline chemotherapy.
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3
作者：
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通讯作者：
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