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Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition
Zha, J Chen, F Dong, H Shi, P Yao, Y Zhang, Y Li, R Wang, S Li, P Wang, W
Zha, J
Chen, F
Dong, H
Shi, P
Yao, Y
Zhang, Y
Li, R
Wang, S
Li, P
Wang, W
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2014-06-11
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Abstract
Background: Disulfiram (DS), an anti-alcoholism drug, demonstrates strong antitumor activity in a copper (Cu)-dependent manner. This study investigates the cytotoxicity of DS/Cu complex in lymphoid malignant cell lines in vitro and in vivo.Method: Raji cells were subjected to different treatments and thereafter MTT assay, flow cytometry were used to determine IC50 and apoptotic status. We also tested the cytotoxicity of DS/Cu in acute lymphoblastic leukemia cell line Molt4 in vitro. In vivo experiments were also performed to demonstrate the anticancer efficacy of DS/Cu in Raji cells xenografted nude mice.Results: In combination with a low concentration (1 μM) of Cu2+, DS induced cytotoxicity in Raji cells with an IC50 of 0.085 ± 0.015 μM and in Molt4 cells with an IC50 of 0.435 ± 0.109 μM. The results of our animal experiments also showed that the mean tumor volume in DS/Cu-treated mice was significantly smaller than that in DS or control group, indicating that DS/Cu inhibits the proliferation of Raji cells in vivo. DS/Cu also induced apoptosis in 2 lymphoid malignant cell lines. After exposure to DS (3.3 μM)/Cu (1 μM) for 24 hours, apoptosis was detected in 81.03 ± 7.91% of Raji cells. DS/Cu induced significant apoptosis in a concentration-dependent manner with the highest apoptotic proportion (DS/Cu: 89.867 ± 4.69%) at a concentration of 2 μM in Molt4 cells. After 24 h exposure, DS/Cu inhibits Nrf2 expression. Flow cytometric analysis shows that DS/Cu induced ROS generation. DS/Cu induced phosphorylation of JNK and inhibits p65 expression as well as Nrf2 expression both in vitro and in vivo. N-acetyl-L-cysteine (NAC), an antioxidant, can partially attenuate DS/Cu complex-induced apoptosis and block JNK activation in vitro. In addition, NAC is able to restore Nrf2 nuclear translocation and p65 expression.Conclusion: Our study manifests that DS/Cu complex targets lymphoid malignant cells in vitro and in vivo. Generation of ROS might be one of core steps in DS/Cu induced apoptosis. Moreover, ROS-related activation of JNK pathway and inhibition of NF-κB and Nrf2 may also contribute to the DS/Cu induced apoptosis. © 2014 Zha et al.; licensee BioMed Central Ltd.
Citation
Zha, J., Chen, F., Dong, H. et al. (2014) Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition, Journal of Translational Medicine, 12, 163. https://doi.org/10.1186/1479-5876-12-163
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PubMed ID
24915933
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Journal article
Language
en
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ISSN
1479-5876
EISSN
1479-5876
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This work was financially supported by National Nature Science Foundation of China, P.R. China (No. 81070425) , The technology program of Guangdong Province, P.R. China (No. 2009B050700028) and President Foundation of Nanfang Hospital (No.2012C007).
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Licence for published version: Creative Commons Attribution 4.0 International