Honokiol Crosses BBB and BCSFB, and Inhibits Brain Tumor Growth in Rat 9L Intracerebral Gliosarcoma Model and Human U251 Xenograft Glioma Model

被引：122

作者：

Wang, Xianhuo ^{[1
,2
]}

Duan, Xingmei ^{[1
,2
]}

Yang, Guangli ^{[1
,2
]}

Zhang, Xiaoyan ^{[1
,2
]}

Deng, Linyu ^{[1
,2
]}

Zheng, Hao ^{[1
,2
]}

Deng, Chongyang ^{[1
,2
]}

Wen, Jiaolin ^{[1
,2
]}

Wang, Ning ^{[1
,2
]}

Peng, Cheng ^{[3
]}

Zhao, Xia ^{[1
,2
]}

Wei, Yuquan ^{[1
,2
]}

Chen, Lijuan ^{[1
,2
,3
]}

机构：

[1] Sichuan Univ, W China Med Sch, W China Hosp, State Key Lab Biotherapy, Chengdu 610064, Peoples R China

[2] Sichuan Univ, W China Med Sch, W China Hosp, Ctr Canc, Chengdu 610064, Peoples R China

[3] Chengdu Univ Tradit Chinese Med, State Key Lab Breeding Base Systemat Res Dev & Ut, Chengdu, Sichuan, Peoples R China

来源：

PLOS ONE | 2011年 / 6卷 / 04期

基金：

中国国家自然科学基金;

关键词：

P-GLYCOPROTEIN; IN-VIVO; MAGNOLIA BARK; BARRIER; THERAPY; AGENT; CELLS; MICE; ANGIOGENESIS; IDENTIFICATION;

D O I：

10.1371/journal.pone.0018490

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background: Gliosarcoma is one of the most common malignant brain tumors, and anti-angiogenesis is a promising approach for the treatment of gliosarcoma. However, chemotherapy is obstructed by the physical obstacle formed by the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Honokiol has been known to possess potent activities in the central nervous system diseases, and anti-angiogenic and anti-tumor properties. Here, we hypothesized that honokiol could cross the BBB and BCSFB for the treatment of gliosarcoma. Methodologies: We first evaluated the abilities of honokiol to cross the BBB and BCSFB by measuring the penetration of honokiol into brain and blood-cerebrospinal fluid, and compared the honokiol amount taken up by brain with that by other tissues. Then we investigated the effect of honokiol on the growth inhibition of rat 9L gliosarcoma cells and human U251 glioma cells in vitro. Finally we established rat 9L intracerebral gliosarcoma model in Fisher 344 rats and human U251 xenograft glioma model in nude mice to investigate the anti-tumor activity. Principal Findings: We showed for the first time that honokiol could effectively cross BBB and BCSFB. The ratios of brain/plasma concentration were respectively 1.29, 2.54, 2.56 and 2.72 at 5, 30, 60 and 120 min. And about 10% of honokiol in plasma crossed BCSFB into cerebrospinal fluid (CSF). In vitro, honokiol produced dose-dependent inhibition of the growth of rat 9L gliosarcoma cells and human U251 glioma cells with IC(50) of 15.61 mu g/mL and 16.38 mu g/mL, respectively. In vivo, treatment with 20 mg/kg body weight of honokiol (honokiol was given twice per week for 3 weeks by intravenous injection) resulted in significant reduction of tumor volume (112.70 +/- 10.16 mm(3)) compared with vehicle group (238.63 +/- 19.69 mm(3), P = 0.000), with 52.77% inhibiting rate in rat 9L intracerebral gliosarcoma model, and (1450.83 +/- 348.36 mm(3)) compared with vehicle group (2914.17 +/- 780.52 mm(3), P = 0.002), with 50.21% inhibiting rate in human U251 xenograft glioma model. Honokiol also significantly improved the survival over vehicle group in the two models (P < 0.05). Conclusions/Significance: This study provided the first evidence that honokiol could effectively cross BBB and BCSFB and inhibit brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. It suggested a significant strategy for offering a potential new therapy for the treatment of gliosarcoma.

引用

页数：12

共 46 条

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