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Biochem Biophys Res Commun. 2016 Jan 15;469(3):716-22. doi: 10.1016/j.bbrc.2015.12.059. Epub 2015 Dec 18.

Pyrvinium selectively induces apoptosis of lymphoma cells through impairing mitochondrial functions and JAK2/STAT5.

Author information

1
Department of Laboratory Medicine, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jing Zhou, People's Republic of China.
2
Department of Haematology, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jing Zhou, People's Republic of China.
3
Department of Clinical Medicine, Medical School of Yangtze University, Jing Zhou, People's Republic of China.
4
Department of Laboratory Medicine, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jing Zhou, People's Republic of China. Electronic address: Changfu.wang@hotmail.com.

Abstract

Targeting mitochondrial respiration has emerged as an attractive therapeutic strategy in blood cancer due to their unique metabolic dependencies. In this study, we show that pyrvinium, a FDA-approved anthelmintic drug, selectively targets lymphoma T-cells though inhibition of mitochondrial functions and JAK2/STAT5. Pyrvinium induces apoptosis of malignant T-cell line Jurkat and primary T-cells from lymphoma patients while sparing T-cells from healthy donors. Increased level of active caspase-3 and decreased levels of Bcl-2 and Mcl-1 were also observed in Jurkat and lymphoma T-cells but not normal T-cells treated with pyrvinium. In addition, pyrvinium impairs mitochondrial functions by inhibit mitochondrial respiration, suppressing mitochondrial respiratory complex I activity, increasing ROS and decreasing ATP levels. However, the effects of pyrvinium were abolished in mitochondrial respiration-deficient Jurkat ρ(0) cells, confirming that pyrvinium acts on lymphoma T-cells via targeting mitochondrial respiration. We further show that lymphoma T-cells derived from patients depend more on mitochondrial respiration than normal T-cells, and this explains the selective toxicity of pyrvinium in lymphoma versus normal T-cells. Finally, we demonstrate that pyrvinium also suppresses JAK2/STAT5 signaling pathway in Jurkat cells. Our study suggests that pyrvinium is a useful addition to T-cell lymphoma treatment, and emphasizes the potential therapeutic value of the differences in the mitochondrial characteristics between malignant and normal T-cells in blood cancer.

KEYWORDS:

JAK2/STAT5; Lymphoma; Mitochondrial respiration; Pyrvinium

PMID:
26707639
DOI:
10.1016/j.bbrc.2015.12.059
[Indexed for MEDLINE]

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