2-Methoxyestradiol interferes with NFκB transcriptional activity in primitive neuroectodermal brain tumors

Implications for management

Addanki P Kumar, Gretchen E. Garcia, Jon Orsborn, Victor A. Levin, Thomas J Slaga

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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 G2/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 NFκB and DNA binding activity is reduced indicating that 2-ME disrupts the NFκB 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 G2/M block, it may enhance the effectiveness of radiation therapy.

Original languageEnglish (US)
Pages (from-to)209-216
Number of pages8
JournalCarcinogenesis
Volume24
Issue number2
DOIs
StatePublished - Feb 1 2003
Externally publishedYes

Fingerprint

Primitive Neuroectodermal Tumors
Brain Neoplasms
Medulloblastoma
Growth
Therapeutics
Nervous System Neoplasms
Apoptosis
14-3-3 Proteins
Cyclin B1
2-methoxyestradiol
Cell Line
G2 Phase
Astrocytoma
DNA Fragmentation
Glioblastoma
Cell Division
Cell Cycle
Radiotherapy
Central Nervous System
Phosphorylation

ASJC Scopus subject areas

  • Cancer Research

Cite this

2-Methoxyestradiol interferes with NFκB transcriptional activity in primitive neuroectodermal brain tumors : Implications for management. / Kumar, Addanki P; Garcia, Gretchen E.; Orsborn, Jon; Levin, Victor A.; Slaga, Thomas J.

In: Carcinogenesis, Vol. 24, No. 2, 01.02.2003, p. 209-216.

Research output: Contribution to journalArticle

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