1.Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling.
Byung Hak KIM ; Yun Sook MIN ; Jung Sook CHOI ; Gyeong Hun BAEG ; Youngsoo KIM ; Jong Wook SHIN ; Tae Yoon KIM ; Sang Kyu YE
Experimental & Molecular Medicine 2011;43(5):313-321
Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma.
Animals
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Antineoplastic Agents/chemistry/*pharmacology
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Apoptosis/drug effects
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Bicyclo Compounds, Heterocyclic/chemistry/*pharmacology
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Cell Line
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Cell Proliferation/drug effects
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Cell Survival/drug effects
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Drosophila/enzymology/metabolism
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Drosophila Proteins/antagonists & inhibitors/metabolism
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Enzyme Activation/*drug effects
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Gene Expression Regulation, Neoplastic/*drug effects
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Humans
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Janus Kinase 3/*antagonists & inhibitors/metabolism
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Lymphoma/enzymology/*metabolism
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Phosphorylation/drug effects
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STAT Transcription Factors/antagonists & inhibitors/metabolism
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STAT3 Transcription Factor/*antagonists & inhibitors/metabolism
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Signal Transduction/*drug effects
2.Inhibition of Janus activated kinase-3 protects against myocardial ischemia and reperfusion injury in mice.
Young Bin OH ; Min AHN ; Sang Myeong LEE ; Hyoung Won KOH ; Sun Hwa LEE ; Suhn Hee KIM ; Byung Hyun PARK
Experimental & Molecular Medicine 2013;45(5):e23-
Recent studies have documented that Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathway can modulate the apoptotic program in a myocardial ischemia/reperfusion (I/R) model. To date, however, limited studies have examined the role of JAK3 on myocardial I/R injury. Here, we investigated the potential effects of pharmacological JAK3 inhibition with JANEX-1 in a myocardial I/R model. Mice were subjected to 45 min of ischemia followed by varying periods of reperfusion. JANEX-1 was injected 1 h before ischemia by intraperitoneal injection. Treatment with JANEX-1 significantly decreased plasma creatine kinase and lactate dehydrogenase activities, reduced infarct size, reversed I/R-induced functional deterioration of the myocardium and reduced myocardial apoptosis. Histological analysis revealed an increase in neutrophil and macrophage infiltration within the infarcted area, which was markedly reduced by JANEX-1 treatment. In parallel, in in vitro studies where neutrophils and macrophages were treated with JANEX-1 or isolated from JAK3 knockout mice, there was an impairment in the migration potential toward interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), respectively. Of note, however, JANEX-1 did not affect the expression of IL-8 and MCP-1 in the myocardium. The pharmacological inhibition of JAK3 might represent an effective approach to reduce inflammation-mediated apoptotic damage initiated by myocardial I/R injury.
Animals
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Apoptosis/drug effects
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Cell Movement/drug effects
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Chemokines/pharmacology
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Heart Function Tests/drug effects
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Inflammation/pathology
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Janus Kinase 3/*antagonists & inhibitors/metabolism
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Macrophages/drug effects/metabolism/pathology
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Male
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Mice
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Mice, Inbred C57BL
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Myocardial Reperfusion Injury/drug therapy/*enzymology/physiopathology/*prevention & control
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Myocardium/enzymology/pathology
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Myocytes, Cardiac/drug effects/metabolism/pathology
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Neutrophils/drug effects/metabolism/pathology
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Quinazolines/pharmacology/therapeutic use