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Synergistic killing of colorectal cancer cells by oxaliplatin and ABT-737.
Raats, Daniëlle A E; de Bruijn, Menno T; Steller, Ernst J A; Emmink, Benjamin L; Borel-Rinkes, Inne H M; Kranenburg, Onno.
Afiliação
  • Raats DA; Department of Surgery, University Medical Center Utrecht, The Netherlands.
Cell Oncol (Dordr) ; 34(4): 307-13, 2011 Aug.
Article em En | MEDLINE | ID: mdl-21468686
BACKGROUND: Oxaliplatin is frequently used in the treatment of metastatic colorectal cancer (CRC). Our previous work shows that oxaliplatin induces the pro-apoptotic protein Noxa in CRC cells. The Bcl2-inhibitor ABT-737 is particularly effective in cells with high Noxa levels. Therefore, we tested whether oxaliplatin and ABT-737 display synergy in killing CRC cells. METHODS: A panel of CRC cell lines was treated with oxaliplatin and ABT-737, either alone or in combination. Apoptosis was measured by FACS analysis of sub-G1 DNA content and by Western blot analysis of caspase-3 processing. Noxa expression was suppressed by lentiviral RNA interference. RESULTS: Oxaliplatin and ABT-737 displayed a strong synergistic apoptotic response, which was dependent on wildtype TP53 and oncogenic KRAS. TP53 and KRAS were required for drug-induced Noxa expression and this was essential for tumor cell apoptosis. Oxaliplatin, but not ABT-737, induced p53 accumulation, but both drugs stimulated Noxa expression. Combination treatment of mice with subcutaneous tumor xenografts drastically reduced tumor volume, while single drug treatment had no effect. CONCLUSION: ABT-737 synergizes with oxaliplatin to kill colorectal cancer cells. This requires induction of Noxa by wildtype TP53 and oncogenic KRAS. Future studies should explore the anti-tumor efficacy of this drug combination in mouse models for spontaneous CRC development and in patient-derived tumor cell cultures and xenografts.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Compostos Organoplatínicos / Sulfonamidas / Compostos de Bifenilo / Neoplasias Colorretais / Nitrofenóis Idioma: En Ano de publicação: 2011 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Compostos Organoplatínicos / Sulfonamidas / Compostos de Bifenilo / Neoplasias Colorretais / Nitrofenóis Idioma: En Ano de publicação: 2011 Tipo de documento: Article