2-Methoxyestradiol interferes with NFκB transcriptional activity in primitive neuroectodermal brain tumors:: implications for management

被引:48
作者
Kumar, AP [1 ]
Garcia, GE
Orsborn, J
Levin, VA
Slaga, TJ
机构
[1] AMC Canc Res Ctr, Ctr Canc Causat & Prevent, Denver, CO 80214 USA
[2] Univ Colorado, Ctr Comprehens Canc, Denver, CO 80214 USA
[3] Univ Texas, MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA
关键词
D O I
10.1093/carcin/24.2.209
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Medulloblastoma (MB) is a primitive neuroectodermal tumor (PNET) of the central nervous system (CNS) and the most common malignant primary brain tumor in children. Currently, poor risk and recurrent MB patients are treated with cytotoxic chemotherapy alone or in combination with surgery and irradiation. In order to improve on therapeutic outcome and reduce toxicity of current treatment strategies, new and novel therapeutic agents are needed for MB patients. To that purpose, we have examined the effect of 2-methoxyestradiol (2-ME), an endogenous non-toxic estrogenic metabolite on the growth of three medulloblastoma cell lines (DAOY, D341 and D283); and two high-grade anaplastic astrocytoma/glioblastoma cell lines, U-87MG and T-98-G. We present evidence to show that 2-ME preferentially inhibits the growth of medulloblastoma cells significantly by blocking cell cycle progression predominantly in G(2)/M phase. 2-ME treatment results in phosphorylation of cdc25C without any significant alterations in the expression of cyclin B1 or p34cdc2. In addition, we observed a decrease in the levels of 14-3-3 proteins following treatment with 2-ME. Furthermore, 2-ME-mediated growth inhibition is accompanied by induction of apoptosis as evidenced by morphological alterations and DNA fragmentation analysis. Of interest is the finding that 2-ME induced apoptosis is not mediated through alterations in the expression of p53 or Bax and that transcriptional activity of NFkappaB and DNA binding activity is reduced indicating that 2-ME disrupts the NFkappaB signaling pathway. These results suggest that 2-ME may prove to be a useful therapeutic agent in the treatment of PNET brain tumors such as medulloblastoma. In addition, as 2-ME inhibits growth predominantly through G(2)/M block, it may enhance the effectiveness of radiation therapy.
引用
收藏
页码:209 / 216
页数:8
相关论文
共 47 条
[1]   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
[2]   SERUM CONCENTRATION AND URINARY-EXCRETION OF CLASSICAL ESTROGENS, CATECHOLESTROGENS AND 2-METHOXYESTROGENS IN NORMAL HUMAN-PREGNANCY [J].
BERG, FD ;
KUSS, E .
ARCHIVES OF GYNECOLOGY AND OBSTETRICS, 1992, 251 (01) :17-27
[3]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[4]   Regulation of p53 downstream genes [J].
El-Deiry, WS .
SEMINARS IN CANCER BIOLOGY, 1998, 8 (05) :345-357
[5]  
FOTSIS T, 1994, NATURE, V368, P237, DOI 10.1038/368237a0
[6]  
GHOSH R, 2003, IN PRESS MELANOMA RE
[7]   Updated results of a pilot study of low dose craniospinal irradiation plus chemotherapy for children under five with cerebellar primitive neuroectodermal tumors (medulloblastoma) [J].
Goldwein, JW ;
Radcliffe, J ;
Johnson, J ;
Moshang, T ;
Packer, RJ ;
Sutton, LN ;
Rorke, LB ;
DAngio, GJ .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 1996, 34 (04) :899-904
[8]   Long-term intellectual outcome in children with posterior fossa tumors according to radiation doses and volumes [J].
Grill, J ;
Renaux, VK ;
Bulteau, C ;
Viguier, D ;
Levy-Piebois, C ;
Sainte-Rose, C ;
Dellatolas, G ;
Raquin, MA ;
Jambaqué, I ;
Kalifa, C .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 1999, 45 (01) :137-145
[9]   PHOSPHORYLATION AND ACTIVATION OF HUMAN CDC25-C BY CDC2 CYCLIN-B AND ITS INVOLVEMENT IN THE SELF-AMPLIFICATION OF MPF AT MITOSIS [J].
HOFFMANN, I ;
CLARKE, PR ;
MARCOTE, MJ ;
KARSENTI, E ;
DRAETTA, G .
EMBO JOURNAL, 1993, 12 (01) :53-63
[10]   Prognostic factors for medulloblastoma [J].
Jenkin, D ;
Al Shabanah, M ;
Al Shail, E ;
Gray, A ;
Hassounah, M ;
Khafaga, Y ;
Kofide, A ;
Mustafa, M ;
Schultz, H .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2000, 47 (03) :573-584