Pan-HDAC inhibition by panobinostat mediates chemosensitization to carboplatin in non-small cell lung cancer via attenuation of EGFR signaling.
Cancer Lett
; 417: 152-160, 2018 03 28.
Article
en En
| MEDLINE
| ID: mdl-29306016
ABSTRACT
Accumulating evidence has implicated the aberrant regulation of histone deacetylases (HDACs) as a nexus for multiple cancer hallmarks and in mediating tumor adaptation and resistance to genotoxic chemotherapy, suggesting a rational pairing of HDAC inhibitors with DNA damaging chemotherapeutic agents in the treatment of human malignancies. Here we report that panobinostat (LBH589), a potent pan-HDAC inhibitor, effectively curbed the proliferation of non-small cell lung cancer (NSCLC) cell lines A549, Calu-1, H226, H460, H838 and SKMES-1 at IC50 concentrations between 4 and 31â¯nmol/L via pleiotropic mechanisms, including crosstalk with EGFR signal transduction cascades. Combination therapy with carboplatin elicited rapid tumor cell kill and effectively restrained anchorage-independent clonogenic survival to a considerably greater extent over either monotherapy. The administration of carboplatin and panobinostat at clinically relevant doses to NOD-SCID xenograft mice drastically stalled disease progression by 92% as compared with negative control (Pâ¯=â¯.0026), which was greater than the 28% and 54% achieved with either carboplatin (Pâ¯=â¯.220) or panobinostat (Pâ¯=â¯.017) alone. These data demonstrate that panobinostat has strong anti-NSCLC activity and chemosensitizes tumors to carboplatin, thus justifying further evaluation of this combination approach in clinical trials.
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1
Base de datos:
MEDLINE
Asunto principal:
Protocolos de Quimioterapia Combinada Antineoplásica
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Carcinoma de Pulmón de Células no Pequeñas
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Ensayos Antitumor por Modelo de Xenoinjerto
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Receptores ErbB
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Neoplasias Pulmonares
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cancer Lett
Año:
2018
Tipo del documento:
Article