TY - JOUR
T1 - Inhibition of SUR1 decreases the vascular permeability of cerebral metastases
AU - Thompson, Eric M.
AU - Pishko, Gregory L.
AU - Muldoon, Leslie L.
AU - Neuwelt, Edward A.
N1 - Funding Information:
Abbreviations: BTB, blood-tumor barrier; DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; NIH, National Institutes of Health; NS, 0.9% NaCl; OHSU, Oregon Health & Science University; SAH, subarachnoid hemorrhage; SCLC, small cell lung carcinoma; SUR1, sulfonylurea receptor 1; VEGF, vascular endothelial growth factor; ZO-1, zona occludens-1 Address all correspondence to: Edward A. Neuwelt, MD, Department of Neurology, Blood-Brain Barrier Program, Oregon Health & Science University, 3181 SW Sam Jackson Parkway Road, L603, Portland, OR 97239. E-mail: neuwelte@ohsu.edu 1This study was supported by a Medical Research Foundation of Oregon Early Clinical Investigator grant to E.M.T. and by a Veterans Administration merit review grant and by National Institutes of Health grants NS053468, CA137488, and NS44687 to E.A.N. No author has any conflict of interest to disclose. Received 9 January 2013; Revised 4 March 2013; Accepted 11 March 2013 Copyright © 2013 Neoplasia Press, Inc. All rights reserved 1522-8002/13/$25.00 DOI 10.1593/neo.13164
PY - 2013/5
Y1 - 2013/5
N2 - Inhibition of sulfonylurea receptor 1 (SUR1) by glyburide has been shown to decrease edema after subarachnoid hemorrhage. We investigated if inhibiting SUR1 reduces cerebral edema due to metastases, the most common brain tumor, and explored the putative association of SUR1 and the endothelial tight junction protein, zona occludens-1 (ZO-1). Nude rats were intracerebrally implanted with small cell lung carcinoma (SCLC) LX1 or A2058 melanoma cells (n = 36). Rats were administered vehicle, glyburide (4.8 μg twice, orally), or dexamethasone (0.35 mg, intravenous). Blood-tumor barrier (BTB) permeability (K trans) was evaluated before and after treatment using dynamic contrastenhanced magnetic resonance imaging. SUR1 and ZO-1 expression was evaluated using immunofluorescence and Western blots. In both models, SUR1 expression was significantly increased (P <.05) in tumors. In animals with SCLC, control mean K trans (percent change ± standard error) was 101.8 ± 36.6%, and both glyburide (-21.4 ± 14.2%, P <.01) and dexamethasone (-14.2 ± 13.1%, P <.01) decreased BTB permeability. In animals with melanoma, compared to controls (117.1 ± 43.4%), glyburide lowered BTB permeability increase (3.2 ± 15.4%, P <.05), while dexamethasone modestly lowered BTB permeability increase (63.1 ± 22.1%, P >.05). Both glyburide (P <.001) and dexamethasone (P <.01) decreased ZO-1 gap formation. By decreasing ZO-1 gaps, glyburide was at least as effective as dexamethasone at halting increased BTB permeability caused by SCLC and melanoma. Glyburide is a safe, inexpensive, and efficacious alternative to dexamethasone for the treatment of cerebral metastasis-related vasogenic edema.
AB - Inhibition of sulfonylurea receptor 1 (SUR1) by glyburide has been shown to decrease edema after subarachnoid hemorrhage. We investigated if inhibiting SUR1 reduces cerebral edema due to metastases, the most common brain tumor, and explored the putative association of SUR1 and the endothelial tight junction protein, zona occludens-1 (ZO-1). Nude rats were intracerebrally implanted with small cell lung carcinoma (SCLC) LX1 or A2058 melanoma cells (n = 36). Rats were administered vehicle, glyburide (4.8 μg twice, orally), or dexamethasone (0.35 mg, intravenous). Blood-tumor barrier (BTB) permeability (K trans) was evaluated before and after treatment using dynamic contrastenhanced magnetic resonance imaging. SUR1 and ZO-1 expression was evaluated using immunofluorescence and Western blots. In both models, SUR1 expression was significantly increased (P <.05) in tumors. In animals with SCLC, control mean K trans (percent change ± standard error) was 101.8 ± 36.6%, and both glyburide (-21.4 ± 14.2%, P <.01) and dexamethasone (-14.2 ± 13.1%, P <.01) decreased BTB permeability. In animals with melanoma, compared to controls (117.1 ± 43.4%), glyburide lowered BTB permeability increase (3.2 ± 15.4%, P <.05), while dexamethasone modestly lowered BTB permeability increase (63.1 ± 22.1%, P >.05). Both glyburide (P <.001) and dexamethasone (P <.01) decreased ZO-1 gap formation. By decreasing ZO-1 gaps, glyburide was at least as effective as dexamethasone at halting increased BTB permeability caused by SCLC and melanoma. Glyburide is a safe, inexpensive, and efficacious alternative to dexamethasone for the treatment of cerebral metastasis-related vasogenic edema.
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U2 - 10.1593/neo.13164
DO - 10.1593/neo.13164
M3 - Article
C2 - 23633925
AN - SCOPUS:84877049950
SN - 1522-8002
VL - 15
SP - 535
EP - 543
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 5
ER -