title: Visualizing the antivascular effect of bortezomib on the hypoxic tumor microenvironment.
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.
authors.affiliation: Department of Radiology, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Ackerstaff
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Fuqiu
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Radiation Oncology, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.
authors.forename: Ligang
authors.initials: L
authors.lastname: Xing
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Current address: Department of Anesthesiology, E-Da Hospital, Yanchau District, Kaohsiung, Taiwan.
authors.forename: Hung Tsung
authors.initials: HT
authors.lastname: Hsiao
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Koutcher
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: C Clifton
authors.initials: CC
authors.lastname: Ling
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Gloria C
authors.initials: GC
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D000069286:Bortezomib / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D003287:Contrast Media; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007089:Image Enhancement; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000069286:Bortezomib
keywords: bortezomib; dynamic contrast enhanced magnetic resonance imaging; endothelial cell; hypoxia