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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

Authors
Lee, SJ; Park, HJ; Kim, YH; Kim, BY; Jin, HS; Kim, HJ; Han, JH; Yim, H; Jeong, SY
Citation
International journal of molecular medicine, 30(2):443-450, 2012
Journal Title
International journal of molecular medicine
ISSN
1107-37561791-244X
Abstract
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.
MeSH terms
AdultAntineoplastic Agents/*pharmacologyApoptosis/drug effects/geneticsBiphenyl Compounds/*pharmacology/toxicityCell Line, TumorDoxorubicin/pharmacology/toxicityDrug Resistance, Neoplasm/geneticsGene ExpressionGene Expression Regulation, NeoplasticGene SilencingGenes, Neurofibromatosis 1HumansMaleNeurofibromatosis 1/drug therapy/genetics/*metabolismNitrophenols/*pharmacology/toxicityPiperazines/pharmacology/toxicitySulfonamides/*pharmacology/toxicityYoung Adultbcl-X Protein/*antagonists & inhibitors/genetics/metabolism
DOI
10.3892/ijmm.2012.1013
PMID
22664653
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pathology
Journal Papers > School of Medicine / Graduate School of Medicine > Medical Genetics
AJOU Authors
김, 보영진, 현석김, 현주한, 재호임, 현이정, 선용
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