Dalaklioglu Selvinaz, Erin Nuray
Akdeniz University, Medical Faculty, Department of Pharmacology, 07070, Antalya, Turkey.
Protein Pept Lett. 2016;23(11):952-957. doi: 10.2174/0929866523666160902114459.
Recent studies document the importance of endothelial dysfunction (ED) in cancer development and metastasis. We previously reported that vascular oxidative stress and inflammation result in ED in animals bearing brain murine metastatic breast carcinoma (BCa). Substance P (SP), a neuropeptide found in sensory nerve terminals, was reported to enhance anti-tumoral effects of conventional treatments. SP was also reported to have anti-oxidative effects. We therefore examined the effects of continuous exposure to low dose SP on vascular ED observed in metastatic BCa. In this study, cells derived from brain metastasis of 4T1 murine BCa (denoted as 4TBM) were used. Female Balb-c mice 8-10 weeks old were divided into following groups: (1) Control (Hanks' balanced salt solution injected), (2) injected with 4TBM orthotopically, (3) injected with 4TBM orthotopically and then treated with SP via an osmotic mini-pumps (0.1 mM, pumping rate 0.11 μl/hr). Thoracic aorta was removed 20-26 days after injection of tumor cells. Isometric tension studies were performed in response to potassium chloride, phenylephrine, acetylcholine (an endothelium-dependent vasodilator), and sodium nitroprusside (an endothelium-independent vasodilator). On one hand, presence of tumor resulted in significant inhibition of vascular response to ACh in untreated mice. On the other, in vivo SP treatment restored the diminished relaxation response to ACh in thoracic aorta rings obtained from metastatic BCa bearing mice. These findings suggest that SP can inhibit tumor-induced ED which might be partly responsible from reported anti-tumoral effects of SP. Furthermore, protective effects of SP on vascular endothelium may prevent cardiovascular diseases in cancer patients.
最近的研究证明了内皮功能障碍（ED）在癌症发生和转移中的重要性。我们之前报道过，血管氧化应激和炎症会导致携带脑转移性小鼠乳腺癌（BCa）的动物出现内皮功能障碍。P物质（SP）是一种在感觉神经末梢发现的神经肽，据报道它能增强传统治疗的抗肿瘤作用。也有报道称SP具有抗氧化作用。因此，我们研究了持续低剂量暴露于SP对转移性BCa中观察到的血管内皮功能障碍的影响。在本研究中，使用了源自4T1小鼠BCa脑转移灶的细胞（记为4TBM）。将8 - 10周龄的雌性Balb - c小鼠分为以下几组：（1）对照组（注射汉克斯平衡盐溶液），（2）原位注射4TBM，（3）原位注射4TBM，然后通过渗透微型泵用SP处理（0.1 mM，泵速0.11 μl/小时）。在注射肿瘤细胞后20 - 26天取出胸主动脉。针对氯化钾、去氧肾上腺素、乙酰胆碱（一种内皮依赖性血管舒张剂）和硝普钠（一种非内皮依赖性血管舒张剂）进行等长张力研究。一方面，肿瘤的存在导致未治疗小鼠的血管对乙酰胆碱的反应受到显著抑制。另一方面，体内SP处理恢复了从携带转移性BCa的小鼠获得的胸主动脉环对乙酰胆碱减弱的舒张反应。这些发现表明，SP可以抑制肿瘤诱导的内皮功能障碍，这可能部分解释了SP所报道的抗肿瘤作用。此外，SP对血管内皮的保护作用可能预防癌症患者的心血管疾病。
