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Radiosensitizing Effect of YM155, a Novel Small-Molecule Survivin Suppressant, in Non–Small Cell Lung Cancer Cell Lines

Authors' Affiliations: ¹ Department of Medical Oncology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan; ² Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Sennan-gun, Osaka, Japan; and ³ Kinki University School of Medicine, Sakai Hospital, Minami-ku Sakai, Osaka, Japan; and ⁴ Institute for Drug Research, Astellas Pharma, Inc., Tsukuba-shi, Ibaraki, Japan

Requests for reprints: Isamu Okamoto, Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan. Phone: 81-72-366-0221; Fax: 81-72-360-5000; E-mail: chi-okamoto{at}dotd.med.kindai.ac.jp.

Purpose: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effect of YM155, a small-molecule inhibitor of survivin expression, on the sensitivity of human non–small cell lung cancer (NSCLC) cell lines to -radiation.

Experimental Design: The radiosensitizing effect of YM155 was evaluated on the basis of cell death, clonogenic survival, and progression of tumor xenografts. Radiation-induced DNA damage was evaluated on the basis of histone H2AX phosphorylation and foci formation.

Results: YM155 induced down-regulation of survivin expression in NSCLC cells in a concentration- and time-dependent manner. A clonogenic survival assay revealed that YM155 increased the sensitivity of NSCLC cells to -radiation in vitro. The combination of YM155 and -radiation induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of histone -H2AX also showed that YM155 delayed the repair of radiation-induced double-strand breaks in nuclear DNA. Finally, combination therapy with YM155 and -radiation delayed the growth of NSCLC tumor xenografts in nude mice to a greater extent than did either treatment modality alone.

Conclusions: These results suggest that YM155 sensitizes NSCLC cells to radiation both in vitro and in vivo, and that this effect of YM155 is likely attributable, at least in part, to the inhibition of DNA repair and enhancement of apoptosis that result from the down-regulation of survivin expression. Combined treatment with YM155 and radiation warrants investigation in clinical trials as a potential anticancer strategy.