Oncotarget

Research Papers:

Visualizing the antivascular effect of bortezomib on the hypoxic tumor microenvironment

Xiaorong Sun, Ellen Ackerstaff, Fuqiu He, Ligang Xing _, Hung Tsung Hsiao, Jason A. Koutcher, C. Clifton Ling and Gloria C. Li

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Oncotarget. 2015; 6:34732-34744. https://doi.org/10.18632/oncotarget.5300

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Abstract

Xiaorong Sun1,2, Ellen Ackerstaff3, Fuqiu He2, Ligang Xing4, Hung Tsung Hsiao2,5, Jason A. Koutcher3, C. Clifton Ling3, Gloria C. Li2,3

1Department of Radiology, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China

2Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

4Department of Radiation Oncology, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China

5Current address: Department of Anesthesiology, E-Da Hospital, Yanchau District, Kaohsiung, Taiwan

Correspondence to:

Ligang Xing, e-mail: [email protected]

Keywords: bortezomib, hypoxia, endothelial cell, dynamic contrast enhanced magnetic resonance imaging

Received: February 06, 2014     Accepted: September 11, 2015     Published: September 23, 2015

ABSTRACT

Bortezomib, a novel proteasome inhibitor, has been approved for treating multiple myeloma and mantle cell lymphoma and studied pre-clinically and clinically for solid tumors. Preferential cytotoxicity of bortezomib was found toward hypoxic tumor cells and endothelial cells in vitro. The purpose of this study is to investigate the role of a pretreatment hypoxic tumor microenvironment on the effects of bortezomib in vitro and ex vivo, and explore the feasibility of dynamic contrast enhanced magnetic resonance imaging (DCE MRI) to noninvasively evaluate the biological effects of bortezomib. It was shown in vitro by Western blot, flow cytometry, and ELISA that bortezomib accumulated HIF-1α in non-functional forms and blocks its hypoxia response in human colorectal cancer cell lines. Ex vivo experiments were performed with fluorescent immunohistochemical staining techniques using multiple endogenous and exogenous markers to identify hypoxia (pimonidazole, HRE-TKeGFP), blood flow/permeability (Hoechst 33342), micro-vessels (CD31 and SMA), apoptosis (cleaved caspase 3) and hypoxia response (CA9). After bortezomib administration, overall apoptosis index was significantly increased and blood perfusion was dramatically decreased in tumor xenografts. More importantly, apoptosis signals were found preferentially located in moderate and severe pretreatment hypoxic regions in both tumor and endothelial cells. Meanwhile, DCE MRI examinations showed that the tumor blood flow and permeability decreased significantly after bortezomib administration. The present study revealed that bortezomib reduces tumor hypoxia response and blood perfusion, thus, presenting antivascular properties. It will be important to determine the hypoxic/perfusion status pre- and during treatment at further translational studies.


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