title: Endothelial NO synthase and reactive oxygen species mediated effect of simvastatin on vessel structure and function: pleiotropic and dose-dependent effect on tumor vascular stabilization.
abstract: Statins have been confirmed with protective effect to microvessels in diabetic retinopathy, implicated as reducing vascular permeability, maintaining endothelial junction integrity and improving blood perfusion, which are surrogate markers of vascular 'normalization', but no data are currently available on efficacy of statins on tumor endothelial functions. Since statins have been shown to exhibit a biphasic dose-related response on biological behaviour of microvessels, we sought to determine whether statins with bipolar concentrations can ameliorate vessel dysfunction and then increase efficiency of chemotherapeutics in Lewis lung carcinoma and B16F10 melanoma models. Our in vitro study showed that simvastatin reduces hypoxia-induced endothelium leakage in human umbilical vein endothelial cells (HUVEC) in a concentration-dependent manner. In tumor-bearing mice, low-dose simvastatin (0.2 mg/kg) induced upregulation of endothelial NO synthase (eNOS) skewed vessels to a pericyte-coated and stable pattern, while high-dose simvastatin (10 mg/kg) remarkably deceased reactive oxygen species (ROS)-induced hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) expression, attenuating VEGF-drived tumor vessel hyperpermeability. These changes ultimately improved intratumoral perfusion and decreased tumor hypoxia. Administration of cisplatin and cyclophosphamide to the simvastatin-treated mice resulted in slower tumor growth. Collectively, simvastatin may promote tumor vessel normalization and show clinical benefit when used in combination with chemotherapeutics.
authors: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P.R. China.
authors: Yeshan
authors: Y
authors: Chen
authors: Sheng
authors: S
authors: Zhang
authors: Gang
authors: G
authors: Peng
authors: Jing
authors: J
authors: Yu
authors: Tao
authors: T
authors: Liu
authors: Rui
authors: R
authors: Meng
authors: Zhenyu
authors: Z
authors: Li
authors: Yanxia
authors: Y
authors: Zhao
authors: Gang
authors: G
authors: Wu
mesh_terms: D043924:Angiogenesis Modulating Agents / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002199:Capillary Permeability; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D043924:Angiogenesis Modulating Agents; D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D009861:Onium Compounds; D017382:Reactive Oxygen Species; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C007517:diphenyleneiodonium; D003520:Cyclophosphamide; D019821:Simvastatin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D002945:Cisplatin