The role of histamine in opening blood-tumor barrier
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Zeng Wang1,2, Xin-jun Cai3, Jing Qin1,4, Fa-Jun Xie1,4, Na Han1,4, Hong-yang Lu1,4
1Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Hangzhou, 310022, P.R. China
2Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, 310022, P.R. China
3Department of Pharmacy, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou, 310003, P.R. China
4Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, P.R. China
Hong-yang Lu, e-mail: [email protected]
Keywords: histamine, H2 receptor, tight junctions-associated proteins, blood-tumor barrier
Received: January 08, 2016 Accepted: March 31, 2016 Published: April 21, 2016
Blood-tumor barrier (BTB) reduce the permeability for drugs into tumor tissues. We found that histamine might serve as an essential regulator of BTB function. Further, we aim to determine the role of H2 receptor expression in BTB permeability, and elucidate the underlying mechanisms thereof. Transmission electron microscopy showed that histamine disrupted the integrity of tight junctions (TJ) and increased the number of pinosomes in the cytoplasm. Horseradish peroxidase (HRP) and trans-endothelial resistance detection (TEER) assays revealed that histamine could open BTB and this action was inhibited by cimetidine. Western blot and immunofluorescence assays showed that histamine decreased the expression of tight junction proteins zonula occluden-1(ZO-1), occludin, and claudin-5. Further, quantitative RT-PCR assay showed that the expression of H2 receptor could represent and predicted histamine-induced BTB permeability. In conclusion, histamine opened BTB by down-regulating the TJ-associated proteins. The levels of H2 receptor expression was correlated with the histamine-induced BTB permeability.
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