| Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug. | |
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MedLine Citation:
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PMID: 20530289 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hypoxia is associated with increased metastatic potential and poor prognosis in solid tumors. In this study, we demonstrated in the murine 5T33MM model that multiple myeloma (MM) cells localize in an extensively hypoxic niche compared with the naive bone marrow. Next, we investigated whether hypoxia could be used as a treatment target for MM by evaluating the effects of a new hypoxia-activated prodrug TH-302 in vitro and in vivo. In severely hypoxic conditions, TH-302 induces G(0)/G(1) cell-cycle arrest by down-regulating cyclinD1/2/3, CDK4/6, p21(cip-1), p27(kip-1), and pRb expression, and triggers apoptosis in MM cells by up-regulating the cleaved proapoptotic caspase-3, -8, and -9 and poly ADP-ribose polymerase while having no significant effects under normoxic conditions. In vivo treatment of 5T33MM mice induces apoptosis of the MM cells within the bone marrow microenvironment and decreases paraprotein secretion. Our data support that hypoxia-activated treatment with TH-302 provides a potential new treatment option for MM. |
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Authors:
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Jinsong Hu; Damian R Handisides; Els Van Valckenborgh; Hendrik De Raeve; Eline Menu; Isabelle Vande Broek; Qian Liu; Jessica D Sun; Ben Van Camp; Charles P Hart; Karin Vanderkerken |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-07 |
Journal Detail:
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Title: Blood Volume: 116 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-03 Completed Date: 2010-10-07 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 1524-7 Citation Subset: AIM; IM |
Affiliation:
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Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Belgium. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anoxia / metabolism* Apoptosis / drug effects* Blotting, Western Bone Marrow / drug effects, metabolism Caspases / metabolism Cell Cycle / drug effects Cell Cycle Proteins / metabolism Cell Proliferation / drug effects Humans Male Mice Mice, Inbred C57BL Multiple Myeloma / drug therapy*, metabolism, pathology* Neovascularization, Pathologic Nitroimidazoles / pharmacology* Oxygen / metabolism* Phosphoramide Mustards / pharmacology* Prodrugs / pharmacology* Tumor Cells, Cultured Vascular Endothelial Growth Factor A / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/Nitroimidazoles; 0/Phosphoramide Mustards; 0/Prodrugs; 0/TH 302; 0/Vascular Endothelial Growth Factor A; 0/vascular endothelial growth factor A, mouse; 7782-44-7/Oxygen; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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