Details

Autor(en) / Beteiligte

• Wang, Lingzhi
• Syn, Nicholas Li-Xun
• Subhash, Vinod Vijay
• Any, Yijia
• Thuya, Win Lwin
• Cheow, Esther Sok Hwee
• Kong, Liren
• Yu, Fenggang
• Peethala, Praveen C.
• Wong, Andrea Li-Ann
• Laljibhai, Hirpara J.
• Chinnathambi, Arunachalam
• Ong, Pei Shi
• Ho, Paul Chi-Lui
• Sethi, Gautam
• Yong, Wei Peng
• Goh, Boon Cher

Titel

Pan-HDAC inhibition by panobinostat mediates chemosensitization to carboplatin in non-small cell lung cancer via attenuation of EGFR signaling

Ist Teil von

• Cancer letters, 2018-03, Vol.417, p.152-160

Ort / Verlag

Ireland: Elsevier B.V

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 31 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 (P = .0026), which was greater than the 28% and 54% achieved with either carboplatin (P = .220) or panobinostat (P = .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. •Panobinostat is active against NSCLC cell lines A549, Calu-1, H226, H460, H838 and SKMES-1 at IC50 values of 4–31 nmol/L.•Panobinostat plus carboplatin yielded synergistic tumor cell kill and suppression of anchorage-independentclonogenic growth.•Combination therapy stalled tumorigenesis in mice by 92% compared with control, carboplatin (28%) or panobinostat (54%) alone.