title: Non-receptor tyrosine kinase inhibitors enhances β-cell survival by suppressing the PKCδ signal transduction pathway in streptozotocin-induced β-cell apoptosis.
abstract: GNF-2 and GNF-5 are members of a new class of non-receptor tyrosine kinases inhibitors that possess excellent selectivity towards imatinib-resistant mutations found in chronic myeloid leukemia patients. On the other hand recent reports implicate abnormal tyrosine kinase signaling in β-cell death in Type I and Type II diabetes. In this work we determined the effects of GNF-2, GNF-5 on pancreatic β-cell death caused by streptozotocin (STZ). STZ treatment causes apoptosis of INS-1 cells by activation of intracellular ROS, c-jun N-terminal kinase (JNK), caspase 3, and caspase 3-dependent activation of protein kinase C delta (PKCδ). GNF-2 and GNF-5 increased cell viability and attenuated STZ-induced intracellular ROS and significantly reduced the activation of JNK, caspase 3, and caspase 3-dependent activation of PKCδ. In studies with intact mice, GFN-2 and GNF-5 prevented the loss of beta cells and the increase in blood glucose produced by STZ-treated control mice. Furthermore, immunohistochemical analysis revealed that GNF-2 and GNF-5 increased insulin protein levels in STZ-treated mice when compared with control mice. These findings suggest that non-receptor tyrosine kinase inhibitors provide a new approach for the treatment of new-onset Type I and Type II diabetes.
authors: Department of Biomedical Science, Graduate School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Departments of Internal Medicine, Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors: Udayakumar
authors: U
authors: Karunakaran
authors: School of Animal BT Science and School of Life Sciences and Biotechnology, Center for Laboratory Animal Resources, Kyungpook National University, Daegu, Republic of Korea.
authors: Si Jun
authors: SJ
authors: Park
authors: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors: Do Youn
authors: do Y
authors: Jun
authors: Life Sciences Research Division, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors: Taebo
authors: T
authors: Sim
authors: Departments of Internal Medicine, Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Republic of Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Medical Center, Daegu, Republic of Korea; Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors: Keun-Gyu
authors: KG
authors: Park
authors: School of Animal BT Science and School of Life Sciences and Biotechnology, Center for Laboratory Animal Resources, Kyungpook National University, Daegu, Republic of Korea. Electronic address: ok4325@knu.ac.kr.
authors: Myoung Ok
authors: MO
authors: Kim
authors: Departments of Internal Medicine, Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Republic of Korea; Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Medical Center, Daegu, Republic of Korea; Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea. Electronic address: leei@knu.ac.kr.
authors: In Kyu
authors: IK
authors: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D051745:Protein Kinase C-delta / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013311:Streptozocin / Q000633:toxicity
chemical_list: D001549:Benzamides; C508526:GNF-2 compound; D007328:Insulin; C000603591:N-(2-hydroxyethyl)-3-(6-((4-(trifluoromethoxy)phenyl)amino)-4-pyrimidinyl)benzamide; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D013311:Streptozocin; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3
keywords: Signal transduction; Type 1 diabetes; Tyrosine kinase inhibitor; β-Cell failure