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Inhibition of Bcl-xL by ABT-737 enhances chemotherapy sensitivity in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumor cells.
MedLine Citation:
PMID:  22664653     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Neurofibromatosis type 1 (NF1) is one of the most commonly inherited autosomal dominant disorders. The malignant peripheral nerve sheath tumor (MPNST) is a major cause of mortality in patients with NF1. In this study, we found that overexpression of Bcl-xL in the established NF1-associated MPNST cell line and primary tissue cultured MPNST cells derived from an NF1 patient was closely associated with anticancer drug resistance of the NF1-associated MPNST cells. We demonstrated that high expression of Bcl-xL in the MPNST cells was caused by a decreased transcriptional expression of the NF1 gene. Downregulation of the NF1 gene by RNA interference (RNAi) induced an increase in Bcl-xL expression and a decrease in its sensitivity to apoptosis in the benign neurofibroma cell line and primary normal cells. These results suggest that an alteration of Bcl-xL expression levels by somatic expression changes in the NF1 locus may contribute to the malignant development of benign tumor tissues or normal tissues to MPNSTs. We further demonstrated that either depletion of Bcl-xL expression by RNAi or inactivation of Bcl-xL by ABT-737, a mimetic of the BH3-only protein BAD, was very effective in sensitizing the MPNST cells to apoptotic cell death by combined treatment with the tested anticancer drug doxorubicin. Notably, a low concentration of ABT-737 and doxorubicin could effectively induce synergistic cytotoxicity in the MPNST cells. These results suggest that pharmacological inhibition of Bcl-xL by ABT-737 in combination with doxorubicin can be a potential therapeutic strategy for the treatment of NF1-associated MPNSTs.
Authors:
Su-Jin Lee; Ho-Jin Park; Young-Hwa Kim; Bo-Young Kim; Hyun-Seok Jin; Hyon J Kim; Jae-Ho Han; Hyunee Yim; Seon-Yong Jeong
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-29
Journal Detail:
Title:  International journal of molecular medicine     Volume:  -     ISSN:  1791-244X     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-6-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9810955     Medline TA:  Int J Mol Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Medical Genetics, School of Medicine, Ajou University, Suwon 443-721, Republic of Korea.
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