title: Honokiol crosses BBB and BCSFB, and inhibits brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model.
abstract: 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 µg/mL and 16.38 µg/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
  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.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Xianhuo
authors.initials: X
authors.lastname: Wang
authors.forename: Xingmei
authors.initials: X
authors.lastname: Duan
authors.forename: Guangli
authors.initials: G
authors.lastname: Yang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Linyu
authors.initials: L
authors.lastname: Deng
authors.forename: Hao
authors.initials: H
authors.lastname: Zheng
authors.forename: Chongyang
authors.initials: C
authors.lastname: Deng
authors.forename: Jiaolin
authors.initials: J
authors.lastname: Wen
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Peng
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002555:Cerebrospinal Fluid / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D018316:Gliosarcoma / Q000188:drug therapy*; D006801:Humans; D017705:Lignans / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D017705:Lignans; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols