Marked anti-tumour activity of the combination of YM155, a novel survivin suppressant, and platinum-based drugs
| Autor: | Kiyoko Kuwata, Kazuhiko Nakagawa, Kentaro Yamanaka, Erina Hatashita, Ken Takezawa, Isamu Okamoto, Takahito Nakahara, Yuki Yamada, Tsutomu Iwasa, Aya Kita, Masahiro Fukuoka, Hiroshi Koutoku, Masao Sasamata |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Drug
Male Cancer Research Programmed cell death Lung Neoplasms endocrine system diseases media_common.quotation_subject Survivin DNA repair Biology Carboplatin Inhibitor of Apoptosis Proteins Histones Anti tumour chemistry.chemical_compound Mice Carcinoma Non-Small-Cell Lung Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Phosphorylation non-small cell lung cancer media_common Mice Inbred BALB C apoptosis Imidazoles Cancer Biological activity medicine.disease YM155 Oncology chemistry Apoptosis Immunology Cancer research Translational Therapeutics Microtubule-Associated Proteins DNA Damage Naphthoquinones |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | Background: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effects of the combination of YM155, a novel small-molecule inhibitor of survivin expression, and platinum compounds (cisplatin and carboplatin) on human non-small cell lung cancer (NSCLC) cell lines. Methods: The anti-cancer efficacy of YM155 in combination with platinum compounds was evaluated on the basis of cell death and progression of tumour xenografts. Platinum compound-induced DNA damage was evaluated by immunofluorescence analysis of histone γ-H2AX. Results: Immunofluorescence analysis of histone γ-H2AX showed that YM155 delayed the repair of double-strand breaks induced in nuclear DNA by platinum compounds. The combination of YM155 and platinum compounds also induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Finally, combination therapy with YM155 and platinum compounds delayed the growth of NSCLC tumour xenografts in nude mice to an extent greater than that apparent with either treatment modality alone. Conclusion: These results suggest that YM155 sensitises tumour cells to platinum compounds both in vitro and in vivo, and that this effect is likely attributable to the inhibition of DNA repair and consequent enhancement of apoptosis. |
| Databáze: | OpenAIRE |
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