BCNU down-regulates anti-apoptotic proteins bcl-xL and Bcl-2 in association with cell death in oligodendroglioma-derived cells.

Abstract

Oligodendroglial differentiation in gliomas is associated with enhanced sensitivity to chemotherapy. Antiapoptotic proteins, Bcl-xL and Bcl-2, are over-expressed in early passage cell lines derived from glioblastomas. Down-regulation of Bcl-xL and Bcl-2 with DNA antisense oligonucleotides promotes cell death in glioblastoma cells. Changes of expression of Bcl-xL and Bcl-2 after chemotherapy treatment have not been studied in glioma subtypes. The current experiments correlate decreased expression of both Bcl-xL and Bcl-2 after BCNU chemotherapy and cell death in two oligodendroglioma-derived cell lines. Expression of Bcl-2 family member proteins Bcl-xL, Bcl-2, and Bax were assessed in glioma cells both before and after chemotherapy treatment. Cell survival was assessed with a crystal violet bioassay. Levels of expression of Bcl-2 and Bcl-xL were elevated in two early passage oligodendroglioma-derived cell lines compared with a non-neoplastic glial cell line. BCNU chemotherapy markedly down-regulated expression of Bcl-xL and Bcl-2 proteins in both oligodendroglioma-derived cell lines. Changes in expression of Bcl-xL and Bcl-2 were associated with the increased sensitivity to chemotherapy. There were no changes noted in expression of Bax after BCNU treatment. Modulation of expression of the anti-apoptotic proteins, Bcl-xL and Bcl-2, in the two oligodendroglioma-derived cell lines was associated with increased sensitivity to BCNU chemotherapy. Down-regulation of Bcl-xL and Bcl-2 resulted in reversal of the ratio of Bax/Bcl-xL and Bax/Bcl-2 and enhanced cell death after treatment with BCNU. Mechanisms that control expression of the anti-apoptotic proteins Bcl-xL and/or Bcl-2 may be effective targets in treatment strategies in patients with malignant gliomas.

• Authors: Richard A Lytle, Zhihong Jiang, Xiao Zheng, Keith M Rich
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 68 Issue 3 Pg. 233-41 (Jul 2004) ISSN: 0167-594X [Print] United States
• PMID: 15332326 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents, Alkylating
• BAX protein, human
• BCL2L1 protein, human
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• bcl-X Protein
• Carmustine

Topics

• Antineoplastic Agents, Alkylating (pharmacology, therapeutic use)
• Apoptosis (drug effects, genetics)
• Brain Neoplasms (drug therapy, genetics, metabolism)
• Carmustine (pharmacology, therapeutic use)
• Cell Line, Tumor
• Down-Regulation
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Neuroglia (drug effects, physiology)
• Oligodendroglioma (drug therapy, genetics, metabolism)
• Proto-Oncogene Proteins (drug effects, genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (drug effects, genetics, metabolism)
• bcl-2-Associated X Protein
• bcl-X Protein