Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism

Tomohiro Aoki, Kazuyuki Shimada, Akihiko Sakamoto, Keiki Sugimoto, Takanobu Morishita, Yuki Kojima, Satoko Shimada, Seiichi Kato, Chisako Iriyama, Shunsuke Kuno, Yasuhiko Harada, Akihiro Tomita, Fumihiko Hayakawa, Hitoshi Kiyoi

研究成果: Article

7 引用 (Scopus)

抄録

Despite improved clinical outcomes of diffuse large B-cell lymphoma, a certain proportion of patients still develop a primary refractory disease. To overcome these lymphomas that are intractable to existing treatment strategies, the tumor microenvironment has been identified as a potential therapeutic target. Here we describe our search for effective drugs for primary refractory lymphoma cells with MYC rearrangement. Through the drug screening of 3,440 known compounds, we identified a unique compound, emetine. This compound was effective against lymphoma cells with MYC rearrangement from two different patients that were co-cultured with cancer associated fibroblasts. Emetine induced the death of these cells with a half maximal inhibitory concentration of 312 nM and 506 nM, respectively. Subsequent analyses of the mechanism of action of emetine showed that the drug induced apoptosis of tumor cells via alteration of glucose metabolism through inhibition of hypoxia inducible factor-1α. Moreover, emetine inhibited the potential of cancer associated fibroblasts to support tumor cell viability in vitro and demonstrated significant inhibition of tumor growth in in vivo analyses. Emetine also induced cell death in other primary refractory lymphoma cells with MYC rearrangement. Our combined data indicate that emetine is a potential promising drug for the treatment of intractable lymphomas, which targets both the tumor and its microenvironment.

元の言語English
ページ(範囲)13085-13098
ページ数14
ジャーナルOncotarget
8
発行部数8
DOI
出版物ステータスPublished - 01-01-2017

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Emetine
B-Cell Lymphoma
Lymphoma
Apoptosis
Tumor Microenvironment
Cell Death
Pharmaceutical Preparations
Hypoxia-Inducible Factor 1
Neoplasms
Preclinical Drug Evaluations
Lymphoma, Large B-Cell, Diffuse
Cell Survival
Therapeutics
Glucose
Growth

All Science Journal Classification (ASJC) codes

  • Oncology

これを引用

Aoki, T., Shimada, K., Sakamoto, A., Sugimoto, K., Morishita, T., Kojima, Y., ... Kiyoi, H. (2017). Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism. Oncotarget, 8(8), 13085-13098. https://doi.org/10.18632/oncotarget.14393
Aoki, Tomohiro ; Shimada, Kazuyuki ; Sakamoto, Akihiko ; Sugimoto, Keiki ; Morishita, Takanobu ; Kojima, Yuki ; Shimada, Satoko ; Kato, Seiichi ; Iriyama, Chisako ; Kuno, Shunsuke ; Harada, Yasuhiko ; Tomita, Akihiro ; Hayakawa, Fumihiko ; Kiyoi, Hitoshi. / Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism. :: Oncotarget. 2017 ; 巻 8, 番号 8. pp. 13085-13098.
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abstract = "Despite improved clinical outcomes of diffuse large B-cell lymphoma, a certain proportion of patients still develop a primary refractory disease. To overcome these lymphomas that are intractable to existing treatment strategies, the tumor microenvironment has been identified as a potential therapeutic target. Here we describe our search for effective drugs for primary refractory lymphoma cells with MYC rearrangement. Through the drug screening of 3,440 known compounds, we identified a unique compound, emetine. This compound was effective against lymphoma cells with MYC rearrangement from two different patients that were co-cultured with cancer associated fibroblasts. Emetine induced the death of these cells with a half maximal inhibitory concentration of 312 nM and 506 nM, respectively. Subsequent analyses of the mechanism of action of emetine showed that the drug induced apoptosis of tumor cells via alteration of glucose metabolism through inhibition of hypoxia inducible factor-1α. Moreover, emetine inhibited the potential of cancer associated fibroblasts to support tumor cell viability in vitro and demonstrated significant inhibition of tumor growth in in vivo analyses. Emetine also induced cell death in other primary refractory lymphoma cells with MYC rearrangement. Our combined data indicate that emetine is a potential promising drug for the treatment of intractable lymphomas, which targets both the tumor and its microenvironment.",
author = "Tomohiro Aoki and Kazuyuki Shimada and Akihiko Sakamoto and Keiki Sugimoto and Takanobu Morishita and Yuki Kojima and Satoko Shimada and Seiichi Kato and Chisako Iriyama and Shunsuke Kuno and Yasuhiko Harada and Akihiro Tomita and Fumihiko Hayakawa and Hitoshi Kiyoi",
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Aoki, T, Shimada, K, Sakamoto, A, Sugimoto, K, Morishita, T, Kojima, Y, Shimada, S, Kato, S, Iriyama, C, Kuno, S, Harada, Y, Tomita, A, Hayakawa, F & Kiyoi, H 2017, 'Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism', Oncotarget, 巻. 8, 番号 8, pp. 13085-13098. https://doi.org/10.18632/oncotarget.14393

Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism. / Aoki, Tomohiro; Shimada, Kazuyuki; Sakamoto, Akihiko; Sugimoto, Keiki; Morishita, Takanobu; Kojima, Yuki; Shimada, Satoko; Kato, Seiichi; Iriyama, Chisako; Kuno, Shunsuke; Harada, Yasuhiko; Tomita, Akihiro; Hayakawa, Fumihiko; Kiyoi, Hitoshi.

:: Oncotarget, 巻 8, 番号 8, 01.01.2017, p. 13085-13098.

研究成果: Article

TY - JOUR

T1 - Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism

AU - Aoki, Tomohiro

AU - Shimada, Kazuyuki

AU - Sakamoto, Akihiko

AU - Sugimoto, Keiki

AU - Morishita, Takanobu

AU - Kojima, Yuki

AU - Shimada, Satoko

AU - Kato, Seiichi

AU - Iriyama, Chisako

AU - Kuno, Shunsuke

AU - Harada, Yasuhiko

AU - Tomita, Akihiro

AU - Hayakawa, Fumihiko

AU - Kiyoi, Hitoshi

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Despite improved clinical outcomes of diffuse large B-cell lymphoma, a certain proportion of patients still develop a primary refractory disease. To overcome these lymphomas that are intractable to existing treatment strategies, the tumor microenvironment has been identified as a potential therapeutic target. Here we describe our search for effective drugs for primary refractory lymphoma cells with MYC rearrangement. Through the drug screening of 3,440 known compounds, we identified a unique compound, emetine. This compound was effective against lymphoma cells with MYC rearrangement from two different patients that were co-cultured with cancer associated fibroblasts. Emetine induced the death of these cells with a half maximal inhibitory concentration of 312 nM and 506 nM, respectively. Subsequent analyses of the mechanism of action of emetine showed that the drug induced apoptosis of tumor cells via alteration of glucose metabolism through inhibition of hypoxia inducible factor-1α. Moreover, emetine inhibited the potential of cancer associated fibroblasts to support tumor cell viability in vitro and demonstrated significant inhibition of tumor growth in in vivo analyses. Emetine also induced cell death in other primary refractory lymphoma cells with MYC rearrangement. Our combined data indicate that emetine is a potential promising drug for the treatment of intractable lymphomas, which targets both the tumor and its microenvironment.

AB - Despite improved clinical outcomes of diffuse large B-cell lymphoma, a certain proportion of patients still develop a primary refractory disease. To overcome these lymphomas that are intractable to existing treatment strategies, the tumor microenvironment has been identified as a potential therapeutic target. Here we describe our search for effective drugs for primary refractory lymphoma cells with MYC rearrangement. Through the drug screening of 3,440 known compounds, we identified a unique compound, emetine. This compound was effective against lymphoma cells with MYC rearrangement from two different patients that were co-cultured with cancer associated fibroblasts. Emetine induced the death of these cells with a half maximal inhibitory concentration of 312 nM and 506 nM, respectively. Subsequent analyses of the mechanism of action of emetine showed that the drug induced apoptosis of tumor cells via alteration of glucose metabolism through inhibition of hypoxia inducible factor-1α. Moreover, emetine inhibited the potential of cancer associated fibroblasts to support tumor cell viability in vitro and demonstrated significant inhibition of tumor growth in in vivo analyses. Emetine also induced cell death in other primary refractory lymphoma cells with MYC rearrangement. Our combined data indicate that emetine is a potential promising drug for the treatment of intractable lymphomas, which targets both the tumor and its microenvironment.

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U2 - 10.18632/oncotarget.14393

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