γ-Secretase inhibitor enhances antitumour effect of radiation in Notch-expressing lung cancer

Mizugaki, H.; Sakakibara-Konishi, J.; Ikezawa, Y.; Kikuchi, J.; Kikuchi, E.; Oizumi, S.; Dang, T. P.; Nishimura, M.

γ-Secretase inhibitor enhances antitumour effect of radiation in Notch-expressing lung cancer

Mizugaki, H.; Sakakibara-Konishi, J.; Ikezawa, Y. et al.

British Journal of Cancer, 2012, 106(12), 1953-1959

Permalink : https://hdl.handle.net/2115/49519

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アクセス権	open access
URI	https://hdl.handle.net/2115/49519
タイトル	γ-Secretase inhibitor enhances antitumour effect of radiation in Notch-expressing lung cancer
著者	Mizugaki, H. ; Sakakibara-Konishi, J. ; Ikezawa, Y. ; Kikuchi, J. ; Kikuchi, E. ; Oizumi, S. ; Dang, T. P. ; Nishimura, M.
著者名 Mizugaki, H.
e-Rad_Researcher 50374278 著者名 Sakakibara-Konishi, J.
著者名 Ikezawa, Y.
著者名 Kikuchi, J.
著者名 Kikuchi, E.
著者名 Oizumi, S.
著者名 Dang, T. P.
e-Rad_Researcher 00208224 著者名 Nishimura, M.
言語	英語
キーワード	Notch
	γ-secretase inhibitor
	radiation
	apoptosis
	non-small-cell lung cancer
発行日	2012-06-05
出版者	Cancer Research UK
収録物名	British Journal of Cancer
巻(号)	106(12)
ページ	1953-1959
抄録	BACKGROUND: Notch receptor has an important role in both development and cancer. We previously reported that inhibition of the Notch3 by γ-secretase inhibitor (GSI) induces apoptosis and suppresses tumour proliferation in non-small-cell lung cancer. Although radiation is reported to induce Notch activation, little is known about the relationship between radiation and Notch pathway. METHODS: We examined the effect of combining GSI and radiation at different dosing in three Notch expressing lung cancer cell lines. The cytotoxic effect of GSI and radiation was evaluated using MTT assay and clonogenic assay in vitro and xenograft models. Expressions of Notch pathway, mitogen-activated protein kinase (MAPK) pathway and Bcl-2 family proteins were investigated using western blot analysis. RESULTS: We discovered that the antitumour effect of combining GSI and radiation was dependent on treatment schedule. γ-Secretase inhibitor administration after radiation had the greatest growth inhibition of lung cancer in vitro and in vivo. We showed that the combination induced apoptosis of lung cancer cell lines through the regulation of MAPK and Bcl-2 family proteins. Furthermore, activation of Notch after radiation was ameliorated by GSI administration, suggesting that treatment with GSI prevents Notch-induced radiation resistance. CONCLUSION: Notch has an important role in lung cancer. Treatment with GSI after radiation can significantly enhance radiation-mediated tumour cytotoxicity.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
権利情報	Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
PISSN	0007-0920
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1038/bjc.2012.178