Visualizing the antivascular effect of bortezomib on the hypoxic tumor microenvironment Journal Article
| Authors: | Sun, X.; Ackerstaff, E.; He, F.; Xing, L.; Hsiao, H. T.; Koutcher, J. A.; Clifton Ling, C.; Li, G. C. |
| Article 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-1' 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. |
| Keywords: | controlled study; protein expression; human cell; drug efficacy; nonhuman; flow cytometry; nuclear magnetic resonance imaging; colorectal cancer; mouse; animal tissue; apoptosis; bortezomib; green fluorescent protein; animal experiment; animal model; in vivo study; caspase 3; in vitro study; tumor xenograft; drug effect; enzyme linked immunosorbent assay; hypoxia; endothelium cell; feasibility study; dosage schedule comparison; western blotting; single drug dose; hoe 33342; pimonidazole; cell hypoxia; drug dose regimen; ex vivo study; tumor vascularization; hypoxia inducible factor 1alpha; drug sensitivity; antiangiogenic activity; non invasive measurement; bioaccumulation; cd31 antigen; smooth muscle actin; tumor microenvironment; tumor blood flow; gadolinium pentetate meglumine; endothelial cell; dynamic contrast enhanced magnetic resonance imaging; human; female; article; colorectal cancer cell line; nuclear magnetic resonance spectrometer |
| Journal Title: | Oncotarget |
| Volume: | 6 |
| Issue: | 33 |
| ISSN: | 1949-2553 |
| Publisher: | Impact Journals |
| Date Published: | 2015-10-27 |
| Start Page: | 34732 |
| End Page: | 34744 |
| Language: | English |
| DOI: | 10.18632/oncotarget.5300 |
| PROVIDER: | scopus |
| PUBMED: | 26416246 |
| PMCID: | PMC4741486 |
| DOI/URL: | |
| Notes: | Export Date: 2 December 2015 -- Source: Scopus |
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