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
N1 - Funding Information:
We would like to thank the Drug Discovery Initiative (The Tokyo University, Tokyo, Japan) for providing the Prestwick and Lopack Chemical Library; Mr. Kuniyoshi Kitou, Ms. Kazuko Matsuba, Ms. Yuko Katayama, and Mr. Yoshiaki Inagaki (Nagoya University) for IHC and FISH work; Ms. Yoko Matsuyama, Ms. Chika Wakamatsu, Ms. Manami Kira, Ms. Rie Kojima, Ms. Yukie Konishi, and Ms. Yuko Kojima, (Nagoya University) for assistance with laboratory work; and Dr. Tomoya Katakai (Niigata University) and Dr. Kunihiko Takeyama (Dana Farber Cancer Institute) for providing cell lines. This work was supported by the Program to Disseminate Tenure Tracking System, MEXT, Japan, by a JSPS Grant-in-Aid for Young Scientists (B) 26860724 and the Practical Research for Innovative Cancer Control, MHLW/AMED, Japan grant to K.Shimada and F.H.
PY - 2017
Y1 - 2017
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
DO - 10.18632/oncotarget.14393
M3 - Article
C2 - 28055963
AN - SCOPUS:85013392287
SN - 1949-2553
VL - 8
SP - 13085
EP - 13098
JO - Oncotarget
JF - Oncotarget
IS - 8
ER -