Inhibition of Bcl-xL by ABT-737 enhances chemotherapy sensitivity in             neurofibromatosis type 1-associated malignant peripheral nerve sheath tumor cells.
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.
Department of Medical Genetics, School of Medicine, Ajou University,                     Suwon 443-721, Republic of Korea.
Su-Jin
SJ
Lee
Ho-Jin
HJ
Park
Young-Hwa
YH
Kim
Bo-Young
BY
Kim
Hyun-Seok
HS
Jin
Hyon J
HJ
Kim
Jae-Ho
JH
Han
Hyunee
H
Yim
Seon-Yong
SY
Jeong
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D008297:Male; D009456:Neurofibromatosis 1 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology* / Q000633:toxicity; D010879:Piperazines / Q000494:pharmacology / Q000633:toxicity; D013449:Sulfonamides / Q000494:pharmacology* / Q000633:toxicity; D055815:Young Adult; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051020:bcl-X Protein; D004317:Doxorubicin