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, 6 (4), e18490

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

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

Xianhuo Wang et al. PLoS One.

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.

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 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/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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Mean plasma concentration-time curve of honokiol in rat plasma (The data from 0 min was omitted).
Figure 2
Figure 2. The percentage of honokiol amount in plasma, brain and other tissues at 30 min post-administration.
Figure 3
Figure 3. Honokiol inhibited the growth and induced apoptosis in rat 9L gliosarcoma and human U251 glioma cells.
A and C, Dose-dependent inhibition of 9L gliosarcoma and U251 glioma cells growth, respectively: cells were exposed to various doses of honokiol for 24 h; B and D, Apoptosis of 9L gliosarcoma and U251 glioma cells, respectively: cells were treated with 16 µg/mL honokiol for 24 h.
Figure 4
Figure 4. Honokiol decreased rat 9L intracerebral tumor and human U251 glioma growth in vivo.
A for rat 9L gliosarcoma model; B for human U251 glioma xenograft model (*, P<0.05; **, P<0.01).
Figure 5
Figure 5. Honokiol prolonged the survival time of 9L intracerebral gliosarcoma rats and human U251 glioma xenograft nude mice.
A for rat 9L gliosarcoma model; B for human U251 glioma xenograft model.
Figure 6
Figure 6. Tumor angiogenesis from human U251 glioma xenograft nude mice was assessed using immunohistochemical staining with anti-CD31 antibody.
Microvessel counting was performed at 200×. Significantly reduced numbers of blood vessels in tumors treated with honokiol in comparison with vehicle. Data represented the mean ± SD of microvessels per high-power field (*, P<0.05 vs. vehicle).
Figure 7
Figure 7. Histological staining of organs of rats with vehicle and high-dose honokiol.
Rats were injected via caudal vein at a dose of 80 mg/kg body weight once a day for 14 days.
Figure 8
Figure 8. Collection of CSF from cisterna magna with a rat.

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