Lumbar puncture-administered resveratrol inhibits STAT3 activation, enhancing autophagy and apoptosis in orthotopic rat glioblastomas
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Song Xue1, Shu Xiao-Hong1, Sha Lin2, Bian Jie2, Wang Li-Li1, Gu Jia-Yao1, Shi Shun1, Li Pei-Nan3, Wu Mo-Li1, Wang Qian1, Chen Xiao-Yan1, Kong Qing-You1, Zhang Peng1, Li Hong1, Liu Jia1
1Liaoning Laboratory of Cancer Genomics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
2Department of Radiology, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China
3Department of Orthopedics, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China
Hong Li, email: [email protected]
Jia Liu, email: [email protected]
Keywords: resveratrol, orthotopic rat glioblastoma, lumbar puncture, STAT3 signaling, cell death
Received: April 07, 2016 Accepted: September 20, 2016 Published: October 3, 2016
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.
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