Cao Chen-Jie, Su Ya, Sun Jian, Wang Gui-Yun, Jia Xiao-Qin, Chen Hua-Sheng, Xu Ai-Hua
Department of Pharmacology, Medical College of Yangzhou University, Yangzhou, Jiangsu 225001, China.
CJ. C. and Y. S. contributed equally to this work.
Iran J Pharm Res. 2019 Spring;18(2):803-811. doi: 10.22037/ijpr.2019.1100637.
The objective of this study is to investigate the anti-tumor effect of exocarp extracts (GBEE) on B16 melanoma bearing mice and its related molecular mechanisms. The B16-F10 melanoma solid tumor model was established in CBL/6J mice. The tumor-bearing mice were treated with GBEE (50, 100, 200 mg/kg), taking cis-Dichlorodiamineplatinum (Ⅱ) (DDP, 3 mg/kg) as positive control and normal saline (NS) as model control. After 17 days of administration, the transplanted tumors was stripped and weighed, and the inhibition rate was calculated. Quantitative Reverse Transcription Polymerase chain reaction (qRT-PCR), Western Blot and immunohistochemistry were applied to detect mRNA and protein levels of related factors in B16 transplanted tumor tissues. The results indicated that GBEE (50, 100, 200 mg/kg) inhibited the growth of B16 transplanted solid tumor in CBL/6J mice. Meanwhile, it inhibited the expression of CD34 and reduced microvessel density (MVD) in a dose-dependent manner. Moreover, GBEE dose-dependently down-regulated the mRNA and protein levels of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor 2 (VEGFR2). The phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) proteins were not changed obviously, but the protein levels of p-PI3K and p-Akt were down-regulated. Overall, the inhibitory effect of GBEE on the growth of B16 melanoma transplant tumor in mice is related to inhibiting angiogenesis, and the mechanism involves the regulation of PI3K/Akt/ HIF-lα/VEGF signaling pathway.
本研究旨在探讨外果皮提取物（GBEE）对荷B16黑色素瘤小鼠的抗肿瘤作用及其相关分子机制。在CBL/6J小鼠中建立B16-F10黑色素瘤实体瘤模型。将荷瘤小鼠分别用GBEE（50、100、200mg/kg）处理，以顺二氯二氨铂（Ⅱ）（DDP，3mg/kg）作为阳性对照，生理盐水（NS）作为模型对照。给药17天后，剥离移植瘤并称重，计算抑瘤率。应用定量逆转录聚合酶链反应（qRT-PCR）、蛋白质免疫印迹法（Western Blot）和免疫组织化学法检测B16移植瘤组织中相关因子的mRNA和蛋白水平。结果表明，GBEE（50、100、200mg/kg）可抑制CBL/6J小鼠B16移植实体瘤的生长。同时，它以剂量依赖性方式抑制CD34的表达并降低微血管密度（MVD）。此外，GBEE剂量依赖性地下调缺氧诱导因子-1α（HIF-1α）、血管内皮生长因子（VEGF）和血管内皮生长因子受体2（VEGFR2）的mRNA和蛋白水平。磷酸肌醇3-激酶（PI3K）和蛋白激酶B（Akt）蛋白无明显变化，但p-PI3K和p-Akt的蛋白水平下调。总体而言，GBEE对小鼠B16黑色素瘤移植瘤生长的抑制作用与抑制血管生成有关，其机制涉及PI3K/Akt/HIF-1α/VEGF信号通路的调节。
