Nuclear factor κB inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos

被引:27
作者
Daroczi, Borbala [3 ]
Kari, Gabor [3 ]
Ren, Qing [3 ]
Dicker, Adam P. [2 ,3 ]
Rodeck, Ulrich [1 ,2 ]
机构
[1] Thomas Jefferson Univ, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
[3] Thomas Jefferson Univ, Dept Radiat Oncol, Philadelphia, PA 19107 USA
关键词
BREAST-CANCER CELLS; ETHYL PYRUVATE; IN-VIVO; CDDO-ME; INFLAMMATORY RESPONSE; LIVER DEGENERATION; INDUCE APOPTOSIS; MICE LACKING; KINASE-BETA; P53;
D O I
10.1158/1535-7163.MCT-09-0198
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Inflammatory changes are a major component of the normal tissue response to ionizing radiation, and increased nuclear factor kappa B (NF-kappa B) activity is an important mediator of inflammatory responses. Here, we used zebrafish embryos to assess the capacity of two different classes of pharmacologic agents known to target NF-kappa B to modify radiation toxicity in the vertebrate organism. These were proteasome inhibitors, including lactacystin, MG132, and PS-341 (Bortezomib/VELCADE), and direct inhibitors of NF-kappa B activity, including ethyl pyruvate (EP) and the synthetic triterpenoid CDDO-TFEA (RTA401), among others. The proteasome inhibitors either did not significantly affect radiation sensitivity of zebrafish embryos (MG132, lactacystin) or rendered zebrafish embryos more sensitive to the lethal effects of ionizing radiation (PS-341). Radio-sensitization by PS-341 was reduced in fish with impaired p53 expression or function but not associated with enhanced expression of select p53 target genes. In contrast, the direct NF-kappa B inhibitors EP and CDDO-TFEA significantly improved overall survival of lethally irradiated zebrafish embryos. In addition, direct NF-kappa B inhibition reduced radiation-induced apoptosis in the central nervous system, abrogated aberrations in body axis development, restored metabolization and secretion of a reporter lipid through the gastrointestinal system, and improved renal clearance compromised by radiation. In contrast to amifostine, EP and CDDO-TFEA not only protected against but also mitigated radiation toxicity when given 1 to 2 hours postexposure. Finally, four additional I kappa B kinase inhibitors with distinct mechanisms of action similarly improved overall survival of lethally irradiated zebrafish embryos. In conclusion, inhibitors of canonical pathways to NF-kappa B activation may be useful in alleviating radiation toxicity in patients. [Mol Cancer Ther 2009;8(9):2625-34]
引用
收藏
页码:2625 / 2634
页数:10
相关论文
共 57 条
[1]   Triterpenoid CDDO-methyl ester inhibits the janus-activated kinase-1 (JAK1)→Signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3 [J].
Ahmad, Rehan ;
Raina, Deepak ;
Meyer, Colin ;
Kufe, Donald .
CANCER RESEARCH, 2008, 68 (08) :2920-2926
[2]  
Ahmed KM, 2007, CURR CANCER DRUG TAR, V7, P335
[3]  
[Anonymous], 1995, ZEBRAFISH BOOK
[4]   EMBRYONIC LETHALITY AND LIVER DEGENERATION IN MICE LACKING THE RELA COMPONENT OF NF-KAPPA-B [J].
BEG, AA ;
SHA, WC ;
BRONSON, RT ;
GHOSH, S ;
BALTIMORE, D .
NATURE, 1995, 376 (6536) :167-170
[5]   tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors [J].
Berghmans, S ;
Murphey, RD ;
Wienholds, E ;
Neuberg, D ;
Kutok, JL ;
Fletcher, CDM ;
Morris, JP ;
Liu, TX ;
Schulte-Merker, S ;
Kanki, JP ;
Plasterk, R ;
Zon, LI ;
Look, AT .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (02) :407-412
[6]   Acquisition of stable inducible up-regulation of nuclear factor-κB by tumor necrosis factor exposure confers increased radiation resistance without increased transformation in breast cancer cells [J].
Braunstein, Steve ;
Formenti, Silvia C. ;
Schneider, Robert J. .
MOLECULAR CANCER RESEARCH, 2008, 6 (01) :78-88
[7]   An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models [J].
Burdelya, Lyudmila G. ;
Krivokrysenko, Vadim I. ;
Tallant, Thomas C. ;
Strom, Evguenia ;
Gleiberman, Anatoly S. ;
Gupta, Damodar ;
Kurnasov, Oleg V. ;
Fort, Farrel L. ;
Osterman, Andrei L. ;
DiDonato, Joseph A. ;
Feinstein, Elena ;
Gudkov, Andrei V. .
SCIENCE, 2008, 320 (5873) :226-230
[8]   Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner [J].
Cardoso, Fatima ;
Durbecq, Virginie ;
Laes, Jean-Francois ;
Badran, Bassam ;
Lagneaux, Laurence ;
Bex, Francoise ;
Desmedt, Christine ;
Willard-Gallo, Karen ;
Ross, Jeffrey S. ;
Burny, Arsene ;
Piccart, Martine ;
Sotiriou, Christos .
MOLECULAR CANCER THERAPEUTICS, 2006, 5 (12) :3042-3051
[9]   The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance [J].
Chauhan, D ;
Li, G ;
Podar, K ;
Hideshima, T ;
Shringarpure, R ;
Catley, L ;
Mitsiades, C ;
Munshi, N ;
Tai, YT ;
Suh, N ;
Gribble, GW ;
Honda, T ;
Schlossman, R ;
Richardson, P ;
Sporn, MB ;
Anderson, KC .
BLOOD, 2004, 103 (08) :3158-3166
[10]   Zebrafish IκB kinase 1 negatively regulates NF-κB activity [J].
Correa, RG ;
Matsui, T ;
Tergaonkar, V ;
Rodriguez-Esteban, C ;
Izpisua-Belmonte, JC ;
Verma, IM .
CURRENT BIOLOGY, 2005, 15 (14) :1291-1295