Marked anti-tumour activity of the combination of YM155, a novel survivin suppressant, and platinum-based drugs
Open Access
- 1 June 2010
- journal article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 103 (1), 36-42
- https://doi.org/10.1038/sj.bjc.6605713
Abstract
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. 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. 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. 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.Keywords
This publication has 48 references indexed in Scilit:
- Phase I and Pharmacokinetic Study of YM155, a Small-Molecule Inhibitor of SurvivinJournal of Clinical Oncology, 2008
- YM155, a Novel Small-Molecule Survivin Suppressant, Induces Regression of Established Human Hormone-Refractory Prostate Tumor XenograftsCancer Research, 2007
- Effect of downregulation of survivin expression on radiosensitivity of human epidermoid carcinoma cellsInternational Journal of Radiation Oncology*Biology*Physics, 2006
- Survivin splice variants regulate the balance between proliferation and cell deathOncogene, 2005
- Cisplatin: mode of cytotoxic action and molecular basis of resistanceOncogene, 2003
- Validating survivin as a cancer therapeutic targetNature Reviews Cancer, 2003
- Differential subcellular localization of functionally divergent survivin splice variantsCell Death & Differentiation, 2002
- Cytokine-regulated expression of survivinin myeloid leukemiaBlood, 2001
- The Hallmarks of CancerCell, 2000
- Requirement for p53 and p21 to Sustain G 2 Arrest After DNA DamageScience, 1998