SOD Mimetics: A Novel Class of Androgen Receptor Inhibitors That Suppresses Castration-Resistant Growth of Prostate Cancer

被引:33
作者
Thomas, Rusha [1 ]
Sharifi, Nima [1 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Hematol Oncol, Dallas, TX 75390 USA
关键词
MANGANESE SUPEROXIDE-DISMUTASE; PIPERIDINE NITROXIDE TEMPOL; DEPRIVATION THERAPY; CELL LINES; EXPRESSION; OVEREXPRESSION; PATHWAY; CHEMOPREVENTION; ADENOCARCINOMA; PROLIFERATION;
D O I
10.1158/1535-7163.MCT-11-0540
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Advanced prostate cancer is the second leading cause of cancer-related deaths among American men. The androgen receptor (AR) is vital for prostate cancer progression, even in the face of castrate levels of serum testosterone following androgen ablation therapy, a mainstay therapy for advanced prostate cancer. Downregulation of superoxide dismutase 2 (SOD2), a major intracellular antioxidant enzyme, occurs progressively during prostate cancer progression to advanced states and is known to promote AR activity in prostate cancer. Therefore, this study investigated the effects of SOD mimetics on AR expression and function in AR-dependent LNCaP, CWR22Rv1, and LAPC-4AD prostate cancer cells. Treatment with Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), a SOD mimetic, not only lowered cellular superoxide levels but also concomitantly attenuated AR transcriptional activity and AR target gene expression in a dose-and time-dependent manner, in the presence and absence of dihydrotestosterone, the major endogenous AR agonist. Inhibition of AR by Tempol was mediated, in large part, by its ability to decrease AR protein via increased degradation, in the absence of any inhibitory effects on other nuclear receptors. Inhibitory effects of Tempol on AR were also reproducible with other SOD mimetics, MnTBAP and MnTMPyP. Importantly, effects of Tempol on AR function were accompanied by significant in vitro and in vivo reduction in castration-resistant prostate cancer (CRPC) survival and growth. Collectively, this study has shown for the first time that SOD mimetics, by virtue of their ability to suppress AR function, may be beneficial in treating the currently incurable CRPC, in which SOD2 expression is highly suppressed. Mol Cancer Ther; 11(1); 87-97. (C) 2011 AACR.
引用
收藏
页码:87 / 97
页数:11
相关论文
共 42 条
[1]  
Baker AM, 1997, PROSTATE, V32, P229, DOI 10.1002/(SICI)1097-0045(19970901)32:4<229::AID-PROS1>3.0.CO
[2]  
2-E
[3]   Molecular alterations in primary prostate cancer after androgen ablation therapy [J].
Best, CJM ;
Gillespie, JW ;
Yi, YJ ;
Chandramouli, GVR ;
Perlmutter, MA ;
Gathright, Y ;
Erickson, HS ;
Georgevich, L ;
Tangrea, MA ;
Duray, PH ;
González, S ;
Velasco, A ;
Linehan, WM ;
Matusik, RJ ;
Price, DK ;
Figg, WD ;
Emmert-Buck, MR ;
Chuaqui, RF .
CLINICAL CANCER RESEARCH, 2005, 11 (19) :6823-6834
[4]  
Bostwick DG, 2000, CANCER, V89, P123, DOI 10.1002/1097-0142(20000701)89:1<123::AID-CNCR17>3.0.CO
[5]  
2-9
[6]   PROOXIDANT STATES AND TUMOR PROMOTION [J].
CERUTTI, PA .
SCIENCE, 1985, 227 (4685) :375-381
[7]   PARTICIPATION OF REACTIVE OXYGEN SPECIES IN THE LYSOPHOSPHATIDIC ACID-STIMULATED MITOGEN-ACTIVATED PROTEIN-KINASE KINASE ACTIVATION PATHWAY [J].
CHEN, QL ;
OLASHAW, N ;
WU, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (48) :28499-28502
[8]   Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance [J].
Dehm, Scott M. ;
Schmidt, Lucy J. ;
Heemers, Hannelore V. ;
Vessella, Robert L. ;
Tindall, Donald J. .
CANCER RESEARCH, 2008, 68 (13) :5469-5477
[9]   Antiproliferative effect of the piperidine nitroxide tempol on neoplastic and nonneoplastic mammalian cell lines [J].
Gariboldi, MB ;
Lucchi, S ;
Caserini, C ;
Supino, R ;
Oliva, C ;
Monti, E .
FREE RADICAL BIOLOGY AND MEDICINE, 1998, 24 (06) :913-923
[10]   Study of in vitro and in vivo effects of the piperidine nitroxide Tempol -: a potential new therapeutic agent for gliomas [J].
Gariboldi, MB ;
Ravizza, R ;
Petterino, C ;
Castagnaro, M ;
Finocchiaro, G ;
Monti, E .
EUROPEAN JOURNAL OF CANCER, 2003, 39 (06) :829-837