Proteasome inhibition with bortezomib enhances activity of topoisomerase I-targeting drugs by NF-kappaB-independent mechanisms.
Anticancer Res
; 26(3A): 1869-76, 2006.
Article
em En
| MEDLINE
| ID: mdl-16827119
ABSTRACT
PURPOSE:
The potentiation of topoisomerase (topo)-I-induced apoptosis by proteasome inhibitors is dependent on the treatment sequence, but not on NF-kappaB. In this study, alternate mechanisms modulating apoptosis induced with the topo I-targeting drug, SN-38, when followed by the proteasome inhibitor bortezomib (PS-341) were investigated. MATERIALS ANDMETHODS:
Human non-small cell lung carcinoma (NSCLC-3) cells transfected with a control vector (NSCLC-3/neo) or a vector containing dominant negative IkappaBalpha (NSCLC-3/mIkappaBalpha) were treated with SN-38 for 1 h followed by PS-341 for 4 h (SN-38 --> PS-341), or with either drug alone. The functional role of the anti-apoptotic protein survivin was tested using NSCLC-3 transfected with myc-tagged wild-type (NSCLC-3/myc-survivin), or dominant negative mutant T34A survivin (NSCLC-3/myc-T34A).RESULTS:
In NSCLC-3/neo or NSCLC-3/mIkappaBalpha cells, treatment with SN-38 --> PS-341 led to down-regulation of the survivin transcript and protein, enhanced apoptosis and reduced (> 3-fold) survival compared to SN-38 or PS-341 alone. In contrast to the cells transfected with wild-type survivin, or the control NSCLC-3/neo, those cells transfected with mutant survivin and treated with SN-38 --> PS-341 exhibited enhanced caspase 9 activity (> 2-fold), caspase 3 (> 2- to 3-fold) activity and cytotoxicity compared to the NSCLC-3/neo cells.CONCLUSION:
In contrast to inhibition of NF-kappaB activity, down-regulation of the anti-apoptotic survivin was correlated with modulation of the sequence-dependent synergistic effects of PS-341 in SN-38-induced apoptosis.
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Base de dados:
MEDLINE
Assunto principal:
Pirazinas
/
Ácidos Borônicos
/
Protocolos de Quimioterapia Combinada Antineoplásica
/
Regulação para Baixo
/
Carcinoma Pulmonar de Células não Pequenas
/
Inibidores da Topoisomerase I
/
Inibidores de Proteassoma
/
Neoplasias Pulmonares
Limite:
Humans
Idioma:
En
Revista:
Anticancer Res
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Estados Unidos