Borneol increases blood–tumour barrier permeability by regulating the expression levels of tight junction-associated proteins

Abstract

Context: Selectively opening the blood–tumour barrier (BTB) is critical to deliver antitumour drugs from blood to tumour tissues. The BTB problem is attributed to the tight junctions (TJs), which consist of several transmembrane proteins.Objective: To investigate whether borneol could open the BTB by affecting TJ-associated proteins ZO-1, occludin, claudin-5 and F-actin in the rat model of C6 glioma.Materials and methods: The plasma and brain tissue of C6 glioma rats were collected at different points after rats were administered with 35 or 140 mg/kg borneol and 0.5% CMC-Na, respectively. The permeability of BTB was assessed by cisplatin extravasation. The mRNA and protein expression levels of TJ-associated proteins were determined by QPCR, ELISA and immunohistochemistry.Results: The cisplatin bioavailability in the brain tissue of C6 glioma rats administered either 35 or 140 mg/kg borneol and 0.5% CMC-Na were 415.07, 227.04 and 192.07 (mg/mL/h), respectively. The mRNA and protein expression levels of ZO-1 and F-actin began to decrease from the time point of 2 min; the lowest levels in the borneol high-dose (46.7% decrease for ZO-1 and 63.3% for F-actin compared with control) and low-dose groups (54.3% for ZO-1; 77.9% for F-actin) appeared at the time points of 30 and 45 min, respectively. Thereafter, the levels were gradually restored to the level of borneol at 0 h. Occludin and claudin-5 expression levels were not significantly modified.Conclusion: Borneol could selectively open the BTB and consequently increase BTB permeability, and this mechanism is associated with the down-regulation of ZO-1 and F-actin.