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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2009-4-17
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pubmed:abstractText |
Hypoxia inducible factor-1 (HIF-1) promotes tumor cell adaptation to microenvironmental stress. HIF-1 is up-regulated in irradiated tumors and serves as a promising target for radiosensitization. We initially confirmed that the orally bioavailable HIF-1 inhibitor PX-478 reduces HIF-1 protein levels and signaling in vitro in a dose-dependent manner and provides direct radiosensitization of hypoxic cancer cells in clonogenic survival assays using C6 glioma, HN5 and UMSCCa10 squamous cells, and Panc-1 pancreatic adenocarcinoma cell lines. However, PX-478 yields striking in vivo tumor sensitization to single-dose irradiation, which cannot be explained by incremental improvement in direct tumor cell killing. We show that PX-478 prevents postradiation HIF-1 signaling and abrogates downstream stromal adaptation in C6 and HN5 reporter xenografts as measured by serial ultrasound, vascular magnetic resonance imaging, and hypoxia response element-specific micro-positron emission tomography imaging. The primacy of indirect PX-478 in vivo effects was corroborated by our findings that (a) either concurrent or early postradiation sequencing of PX-478 provides roughly equivalent sensitization and (b) constitutive vascular endothelial growth factor expression maintains refractory tumor vessel function and progression following combined radiation and PX-478. These results confirm that disruption of postradiation adaptive HIF-1 signaling by PX-478 imparts increased therapeutic efficacy through blockade of HIF-1-dependent reconstitution of tumor stromal function. Successful translation of targeted HIF-1 radiosensitization to the clinical setting will require specific consideration of tumor microenvironmental effects and mechanisms.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-10749844,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-11033187,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-11100117,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-11308256,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-11452123,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-11595178,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-12153983,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-12750523,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-12778166,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-12957288,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-13130303,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-15026543,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-15141023,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-15342393,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-15378285,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-15570005,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-15833863,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-15950901,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-15967100,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-16098463,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-16162966,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-16199320,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-16457965,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-17118889,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-18202012,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-389899,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-6463146,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-8640781,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19372568-8813149
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/2-amino-3-(4'-N,N-bis(2-chloroethyl)...,
http://linkedlifedata.com/resource/pubmed/chemical/HIF1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Hif1a protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoxia-Inducible Factor 1, alpha...,
http://linkedlifedata.com/resource/pubmed/chemical/Mustard Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Phenylpropionates,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Endothelial Growth Factor A
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
1535-7163
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pubmed:author |
pubmed-author:AlauddinMianM,
pubmed-author:BanksonJamesJ,
pubmed-author:BornmannWilliamW,
pubmed-author:GelovaniJuriJ,
pubmed-author:KooM YMY,
pubmed-author:LemosRobertR,
pubmed-author:MukhopadhayUdayU,
pubmed-author:NishiiRyuichiR,
pubmed-author:OhJunghwanJ,
pubmed-author:PengZhenghongZ,
pubmed-author:PowisGarthG,
pubmed-author:SchwartzDavid LDL,
pubmed-author:SoghomonyanSurenS,
pubmed-author:Thitai-KumarArunA,
pubmed-author:VolginAndreiA,
pubmed-author:WilliamsRyanR
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pubmed:issnType |
Print
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pubmed:volume |
8
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
947-58
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pubmed:dateRevised |
2010-12-3
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pubmed:meshHeading |
pubmed-meshheading:19372568-Humans,
pubmed-meshheading:19372568-Animals,
pubmed-meshheading:19372568-Mice,
pubmed-meshheading:19372568-Head and Neck Neoplasms,
pubmed-meshheading:19372568-Pancreatic Neoplasms,
pubmed-meshheading:19372568-Glioma,
pubmed-meshheading:19372568-Adenocarcinoma,
pubmed-meshheading:19372568-Phenylpropionates,
pubmed-meshheading:19372568-Carcinoma, Squamous Cell,
pubmed-meshheading:19372568-Tumor Cells, Cultured,
pubmed-meshheading:19372568-Mustard Compounds,
pubmed-meshheading:19372568-Whole-Body Irradiation,
pubmed-meshheading:19372568-Cell Hypoxia
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