Xue Song, Xiao-Hong Shu, Lin Sha, Jie Bian, Li-Li Wang, Jia-Yao Gu, Shun Shi, Pei-Nan Li, Mo-Li Wu, Qian Wang, Xiao-Yan Chen, Qing-You Kong, Peng Zhang, Hong Li, Jia Liu
Liaoning Laboratory of Cancer Genomics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
Department of Radiology, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China.
Oncotarget. 2016 Nov 15;7(46):75790-75799. doi: 10.18632/oncotarget.12414.
Trans-resveratrol suppresses glioblastoma growth in vitro, but its effects on intracranial glioblastomas remain untested. Resveratrol crosses the blood-brain barrier, and lumbar puncture (LP) greatly increases its bioavailability in rat brains; therefore, we investigated the effectiveness of LP-administered resveratrol on orthotopic rat glioblastomas. Twenty-four tumor-bearing rats were separated into two groups: Group 1 receiving 100 μl saline containing 0.3% DMSO and Group 2 receiving 100 μl resveratrol (300 μM). Treatments started 3 days after transplantation in 2-day intervals until death. Intracranial drug availabilities, tumor sizes, average life spans and the impacts on STAT3 signaling, apoptosis and autophagy rates were evaluated. MRI imaging revealed that average tumor size in the LP group (495.8 ± 22.3 mm2) was smaller than the control groups (810.3 ± 56.4 mm2; P<0.05). The mean survival time in the LP group (22.2 ± 2.1 d) was longer than control animals (16.0 ± 1.8 d; P<0.05). LP resveratrol-treated glioblastomas showed less Cyclin D1 staining, enhanced autophagy with up-regulated LC3 and Beclin1 expression, and widely distributed apoptotic foci around tumor capillaries with suppressed STAT3 expression and nuclear translocation. In conclusion, LP-delivered resveratrol efficiently inhibited orthotopic rat glioblastoma growth by inactivating STAT3 signaling and enhancing autophagy and apoptosis.
反式白藜芦醇在体外可抑制胶质母细胞瘤的生长，但其对颅内胶质母细胞瘤的影响尚未得到验证。白藜芦醇可穿过血脑屏障，腰椎穿刺（LP）可显著提高其在大鼠脑中的生物利用度；因此，我们研究了经LP给予白藜芦醇对原位大鼠胶质母细胞瘤的疗效。将24只荷瘤大鼠分为两组：第1组接受含0.3%DMSO的100μl生理盐水，第2组接受100μl白藜芦醇（300μM）。移植后3天开始治疗，每隔2天进行一次，直至死亡。评估颅内药物可及性、肿瘤大小、平均寿命以及对STAT3信号传导、凋亡和自噬率的影响。MRI成像显示，LP组的平均肿瘤大小（495.8±22.3mm2）小于对照组（810.3±56.4mm2；P<0.05）。LP组的平均生存时间（22.2±2.1天）长于对照动物（16.0±1.8天；P<0.05）。经LP白藜芦醇治疗的胶质母细胞瘤显示细胞周期蛋白D1染色减少，自噬增强，LC3和Beclin1表达上调，肿瘤毛细血管周围凋亡灶广泛分布，STAT3表达和核转位受到抑制。总之，经LP给予的白藜芦醇通过使STAT3信号失活并增强自噬和凋亡，有效抑制了原位大鼠胶质母细胞瘤的生长。
