Synergistic antitumor effect between vorinostat and topotecan in small cell lung cancer cells is mediated by generation of reactive oxygen species and DNA damage-induced apoptosis
| Autor: | Alessandro Desideri, Elena Di Gennaro, Silvia Castelli, Alfredo Budillon, Francesca Bruzzese, Monia Rocco |
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| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Lung Neoplasms DNA damage medicine.drug_class Type I Apoptosis Pharmacology Hydroxamic Acids Histone Deacetylases Cell Line Topoisomerase I Inhibitors DNA Damage Humans Cell Line Tumor Reactive Oxygen Species Camptothecin Small Cell Lung Carcinoma DNA Topoisomerases Type I Antineoplastic Combined Chemotherapy Protocols Topotecan Drug Synergism Cell Cycle medicine Vorinostat Tumor biology Settore BIO/11 Topoisomerase Histone deacetylase inhibitor Oncology biology.protein DNA fragmentation DNA Topoisomerases medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 8:3075-3087 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-09-0254 |
| Popis: | The topoisomerase-I (topo-I) inhibitor topotecan, derivative of camptothecin, is the only registered drug for relapsed small cell lung cancer (SCLC). The histone deacetylase inhibitor vorinostat has shown preclinical and clinical antitumor activities in hematologic malignancies and solid tumors, including SCLC, and has recently been approved for the treatment of cutaneous T-cell lymphomas. In this study, we analyzed the antitumor effect of vorinostat combined with topotecan or camptothecin in topo-I inhibitor-sensitive H209 and inhibitor-resistant H526 SCLC cells. Simultaneous or sequential exposure (24 h delay) to either agent resulted in strong synergistic cytotoxic effect in both cell lines, as shown by calculating combination index, and confirmed by growth in soft agar. Combination treatments increased S-phase cell cycle arrest paralleled by apoptosis as measured by hypodiploid peak formation, Annexin V binding, DNA fragmentation, and mitochondria destruction. The apoptotic process was triggered by a caspase-dependent mechanism and can be ascribed to the phosphorylation of H2AX, a reporter of DNA double-strand breaks. These effects were paralleled by an increase of topo-I/DNA covalent complexes induced by combination treatment and suggest a potentiation by vorinostat of topotecan-induced DNA damage. Finally, oxidative injury played a significant functional role in the observed enhanced lethality because coadministration of the antioxidant N-acetyl-l-cysteine blocked reactive oxygen species generation, apoptosis, and mitochondria destruction induced by the vorinostat/topotecan combination. To our knowledge, this is the first demonstration of a synergistic antitumor effect between topotecan and vorinostat in SCLC. Because no well-established treatment is available for recurrent SCLC patients, our results indicate that this drug combination should be explored clinically. [Mol Cancer Ther 2009;8(11):3075–87] |
| Databáze: | OpenAIRE |
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