title: Pyrvinium selectively induces apoptosis of lymphoma cells through impairing mitochondrial functions and JAK2/STAT5.
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.
authors.affiliation: Department of Laboratory Medicine, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jing Zhou, People's Republic of China.
authors.forename: Meifang
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Department of Haematology, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jing Zhou, People's Republic of China.
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jing Zhou, People's Republic of China.
authors.forename: Yizheng
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Clinical Medicine, Medical School of Yangtze University, Jing Zhou, People's Republic of China.
authors.forename: Pasupati
authors.initials: P
authors.lastname: Rajoria
authors.affiliation: 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.
authors.forename: Changfu
authors.initials: C
authors.lastname: Wang
mesh_terms: D000871:Anthelmintics / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D019069:Cell Respiration / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D019169:Jurkat Cells; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria; D011774:Pyrvinium Compounds / Q000008:administration & dosage*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000871:Anthelmintics; D000970:Antineoplastic Agents; D011774:Pyrvinium Compounds; D050799:STAT5 Transcription Factor; C024631:pyrvinium; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: JAK2/STAT5; Lymphoma; Mitochondrial respiration; Pyrvinium