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International Journal of Clinical Oncology

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01-04-2017 | Original Article

Combined antitumor effect of γ-secretase inhibitor and ABT-737 in Notch-expressing non-small cell lung cancer

Authors: Jun Sakakibara-Konishi, Yasuyuki Ikezawa, Satoshi Oizumi, Junko Kikuchi, Eiki Kikuchi, Hidenori Mizugaki, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura

Published in: International Journal of Clinical Oncology | Issue 2/2017

Abstract

Background

Inhibition of Notch by γ-secretase inhibitor (GSI) has been shown to have an antitumor effect in Notch-expressing non-small cell lung cancer (NSCLC) and to induce apoptosis through modulation of Bcl-2 family proteins. In particular, Bim, a BH3-only member of the Bcl-2 family of proteins, has an important role in the induction of apoptosis in NSCLC when cells are treated with GSI. ABT-737, a BH3-only mimetic, targets the pro-survival Bcl-2 family and also induces apoptosis.

Methods

The Notch-expressing NSCLC cell lines H460, A549, H1793, and HCC2429 were used. The combined antitumor effect of GSI and ABT-737 was evaluated using the MTT proliferation assay in vitro and in xenograft mouse models. The expression of the Notch pathway and Bcl-2 family was analyzed using Western blotting analysis when cells were treated with a single drug treatment or a combination treatment.

Results

GSI XX or ABT-737 alone inhibited cell proliferation in a dose-dependent manner, and combination drug treatment showed a synergistic antitumor effect in vitro. In vivo, this drug combination significantly suppressed tumor proliferation compared to the single drug treatment. Phospho-Bcl-2 was downregulated and Bax was upregulated by both the single and combination drug treatments. Bim was induced by a single drug treatment and was enhanced by combination treatment. Combination treatment-induced apoptosis was decreased by Bim inhibition, suggesting that the antitumor effect of the drug combination was dependent on Bim.

Conclusion

Based on our data, we propose that the combination treatment is a promising strategy for NSCLC therapy.

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Title: Combined antitumor effect of γ-secretase inhibitor and ABT-737 in Notch-expressing non-small cell lung cancer
Authors: Jun Sakakibara-Konishi
Yasuyuki Ikezawa
Satoshi Oizumi
Junko Kikuchi
Eiki Kikuchi
Hidenori Mizugaki
Ichiro Kinoshita
Hirotoshi Dosaka-Akita
Masaharu Nishimura
Publication date: 01-04-2017
Publisher: Springer Japan
Published in: International Journal of Clinical Oncology / Issue 2/2017
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI: https://doi.org/10.1007/s10147-016-1060-3

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Abstract

Background

Methods

Results

Conclusion

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