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

Abstract

BackgroundGliosarcoma 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.MethodologiesWe 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 FindingsWe 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 IC50 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 mm3) compared with vehicle group (238.63±19.69 mm3, P = 0.000), with 52.77% inhibiting rate in rat 9L intracerebral gliosarcoma model, and (1450.83±348.36 mm3) compared with vehicle group (2914.17±780.52 mm3, 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/SignificanceThis 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.

c-Myc is a novel target of cell cycle arrest by honokiol in prostate cancer cells

“…1A) at pharmacological doses. 14,23,26 The present study extended these finding by demonstrating dose-dependent cell viability inhibition by HNK in additional human prostate cancer cell lines, including 22Rv1 (a castration-resistant prostate cancer cell line with expression of AR splice variants) and VCaP cells (a prostate cancer cell line with wild-type AR expression), and Myc-CaP cell line derived from prostate tumor of a transgenic mouse 27 ( Fig. 1B).…”

“…9 Bai et al 10 were the first to provide in vivo evidence for anticancer activity of HNK in angiosarcoma. In vivo tumor growth inhibitory effect of HNK was subsequently extended to solid tumor models, including colorectal, 11 prostate, 12 breast, 13 and brain 14 tumors. HNK or its liposomal preparation was also shown to inhibit metastasis in vivo in different preclinical models.…”

Honokiol Attenuates Oligomeric Amyloid β1-42-Induced Alzheimer’s Disease in Mice Through Attenuating Mitochondrial Apoptosis and Inhibiting the Nuclear Factor Kappa-B Signaling Pathway

“…In addition, honokiol has been found to improve learning and memory through preserving cholinergic neurons in the brain of senescence-accelerated prone mouse strain 8 (SAMP8) mice [14] and inhibiting the activity of acetylcholinesterase scopolamine-treated mice [15]. Importantly, Wang and colleagues have demonstrated that honokiol has the ability to cross the blood-brain barrier (BBB) [16], which enabled it to be a candidate for AD treatment. However, no study has reported the effects of honokiol in Aβ-accumulation-based cognition deficiency.…”

Honokiol improves learning and memory impairments induced by scopolamine in mice

“…1), isolated from the barks of Magnolia officinalis, has the ability to cross the blood-brain barrier (Wang et al, 2011). Pharmacologically, honokiol possesses diverse biological activities, including anxiolytic (Kuribara et al, 1999), analgesic (Lin et al, 2009), antidepressant (Xu et al, 2008), antithrombotic (Hu et al, 2005), antimicrobial (Ho et al, 2001), antispasmodic (Ko et al, 2003), anti-tumorigenic (Fried and Arbiser, 2009), and neuroprotective (Zhang et al, 2013) properties.…”