Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines

Tsutomu Iwasa, Isamu Okamoto, Minoru Suzuki, Takahito Nakahara, Kentaro Yamanaka, Erina Hatashita, Yuki Yamada, Masahiro Fukuoka, Koji Ono, Kazuhiko Nakagawa

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

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 γ-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 γ-radiation in vitro. The combination of YM155 and γ-radiation induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of histone γ-H2AX also showed that YM155 delayed the repair of radiation-induced double-strand breaks in nuclear DNA. Finally, combination therapy with YM155 and γ-radiation delayed the growth of NSCLC tumor xenografts in nude mice to a reater extent than did either treatment modality alone. onclusions: These results suggest thatYM155 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.

Original languageEnglish
Pages (from-to)6496-6504
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number20
DOIs
Publication statusPublished - Oct 15 2008
Externally publishedYes

Fingerprint

Radiation-Sensitizing Agents
Non-Small Cell Lung Carcinoma
Radiation
Cell Line
Heterografts
Histones
Down-Regulation
Inhibitor of Apoptosis Proteins
Neoplasms
Survival
Therapeutics
Nude Mice
Caspase 3
DNA Repair
DNA Damage
Fluorescent Antibody Technique
Cell Death
Research Design
Cell Count
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines. / Iwasa, Tsutomu; Okamoto, Isamu; Suzuki, Minoru; Nakahara, Takahito; Yamanaka, Kentaro; Hatashita, Erina; Yamada, Yuki; Fukuoka, Masahiro; Ono, Koji; Nakagawa, Kazuhiko.

In: Clinical Cancer Research, Vol. 14, No. 20, 15.10.2008, p. 6496-6504.

Research output: Contribution to journalArticle

Iwasa, T, Okamoto, I, Suzuki, M, Nakahara, T, Yamanaka, K, Hatashita, E, Yamada, Y, Fukuoka, M, Ono, K & Nakagawa, K 2008, 'Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines', Clinical Cancer Research, vol. 14, no. 20, pp. 6496-6504. https://doi.org/10.1158/1078-0432.CCR-08-0468
Iwasa, Tsutomu ; Okamoto, Isamu ; Suzuki, Minoru ; Nakahara, Takahito ; Yamanaka, Kentaro ; Hatashita, Erina ; Yamada, Yuki ; Fukuoka, Masahiro ; Ono, Koji ; Nakagawa, Kazuhiko. / Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 20. pp. 6496-6504.
@article{7ea087db7d344036b9f9fb8c606259ec,
title = "Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines",
abstract = "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 γ-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 γ-radiation in vitro. The combination of YM155 and γ-radiation induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of histone γ-H2AX also showed that YM155 delayed the repair of radiation-induced double-strand breaks in nuclear DNA. Finally, combination therapy with YM155 and γ-radiation delayed the growth of NSCLC tumor xenografts in nude mice to a reater extent than did either treatment modality alone. onclusions: These results suggest thatYM155 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.",
author = "Tsutomu Iwasa and Isamu Okamoto and Minoru Suzuki and Takahito Nakahara and Kentaro Yamanaka and Erina Hatashita and Yuki Yamada and Masahiro Fukuoka and Koji Ono and Kazuhiko Nakagawa",
year = "2008",
month = "10",
day = "15",
doi = "10.1158/1078-0432.CCR-08-0468",
language = "English",
volume = "14",
pages = "6496--6504",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "20",

}

TY - JOUR

T1 - Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines

AU - Iwasa, Tsutomu

AU - Okamoto, Isamu

AU - Suzuki, Minoru

AU - Nakahara, Takahito

AU - Yamanaka, Kentaro

AU - Hatashita, Erina

AU - Yamada, Yuki

AU - Fukuoka, Masahiro

AU - Ono, Koji

AU - Nakagawa, Kazuhiko

PY - 2008/10/15

Y1 - 2008/10/15

N2 - 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 γ-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 γ-radiation in vitro. The combination of YM155 and γ-radiation induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of histone γ-H2AX also showed that YM155 delayed the repair of radiation-induced double-strand breaks in nuclear DNA. Finally, combination therapy with YM155 and γ-radiation delayed the growth of NSCLC tumor xenografts in nude mice to a reater extent than did either treatment modality alone. onclusions: These results suggest thatYM155 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.

AB - 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 γ-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 γ-radiation in vitro. The combination of YM155 and γ-radiation induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of histone γ-H2AX also showed that YM155 delayed the repair of radiation-induced double-strand breaks in nuclear DNA. Finally, combination therapy with YM155 and γ-radiation delayed the growth of NSCLC tumor xenografts in nude mice to a reater extent than did either treatment modality alone. onclusions: These results suggest thatYM155 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.

UR - http://www.scopus.com/inward/record.url?scp=58149197153&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149197153&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-08-0468

DO - 10.1158/1078-0432.CCR-08-0468

M3 - Article

C2 - 18927289

AN - SCOPUS:58149197153

VL - 14

SP - 6496

EP - 6504

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 20

ER -