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Jessica Guenzle, Louisa J Wolf, Nicklas W C Garrelfs, Jonathan M Goeldner, Nadja Osterberg, Cora R Schindler, Joseph E Saavedra, Astrid Weyerbrock
Glioblastoma is associated with poor survival and a high recurrence rate in patients due to inevitable uncontrolled infiltrative tumor growth. The elucidation of the molecular mechanisms may offer opportunities to prevent relapses. In this study we investigated the role of the activating transcription factor 3 (ATF3) in migration of GBM cells in vitro. RNA microarray revealed that gene expression of ATF3 is induced by a variety of chemotherapeutics and experimental agents such as the nitric oxide donor JS-K (O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate)...
2017: Cell Death Discovery
Ray Dong, Xueqian Wang, Huan Wang, Zhengyun Liu, Jie Liu, Joseph E Saavedra
JS-K is a novel anticancer nitric oxide (NO) prodrug effective against a variety of cancer cells, including the inhibition of AM-1 hepatoma cell growth in rats. To further evaluate anticancer effects of JS-K, human hepatoma Hep3B cells were treated with JS-K and the compound control JS-43-126 at various concentrations (0-100μM) for 24h, and cytotoxicity was determined by the MTS assay. The compound control JS-43-126 was not cytotoxic to Hep3B cells at concentrations up to 100μM, while the LC50 for JS-K was about 10μM...
April 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Rongfang Xue, Jianbing Wu, Xiaojun Luo, Yan Gong, Yun Huang, Xinxin Shen, Honghua Zhang, Yihua Zhang, Zhangjian Huang
A novel class of O(2)-(2,4-dinitrophenyl)-1-[N,N-bis(2-substituted ethyl)amino]diazen-1-ium-1,2-diolates 4-6 were designed, synthesized, and biologically evaluated. The most active compound 6 caused significant DNA damage by releasing N,N-bis(2-TsO ethyl)amine and two molecules of nitric oxide (NO) after activation by GST/GSH in cancer cells, being more cytotoxic against three cancer cell lines than a well-known diazeniumdiolate-based anticancer agent JS-K, suggesting that the strategy has potential to extend to other O(2)-derived diazeniumdiolates to improve anticancer activity...
October 4, 2016: Organic Letters
Jessica Günzle, Nadja Osterberg, Joseph E Saavedra, Astrid Weyerbrock
The nitric oxide (NO) donor JS-K is specifically activated by glutathione S-transferases (GSTs) in GST-overexpressing cells. We have shown the induction of cell death in glioblastoma multiforme (GBM) cells at high JS-K doses but the mechanism remains unclear. The aim of this study was to determine whether NO-induced cell death is triggered by induction of apoptotic or necrotic pathways. For the first time, we demonstrate that NO induces cell death via mitotic catastrophe (MC) with non-apoptotic mechanisms in GBM cells...
September 1, 2016: Cell Death & Disease
Ling Liu, Dongmei Wang, Jiangang Wang, Shuying Wang
Hepatocellular carcinoma is one of the most common and deadly forms of human malignancies. JS-K, O(2)-(2, 4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1, 2-diolate, has the ability to induce apoptosis of tumor cell lines. In the present study, JS-K inhibited the proliferation of HepG2 cells in a time- and concentration-dependent manner and significantly induced apoptosis. JS-K enhanced the ratio of Bax-to-Bcl-2, released of cytochrome c (Cyt c) from mitochondria and the activated caspase-9/3...
April 2016: Journal of Biochemical and Molecular Toxicology
Mingning Qiu, Lieqian Chen, Guobin Tan, Longzhi Ke, Sai Zhang, Hege Chen, Jianjun Liu
Reactive oxygen species (ROS) and cellular oxidant stress are regulators of cancer cells. The alteration of redox status, which is induced by increased generation of ROS, results in increased vulnerability to oxidative stress. The aim of this study is to investigate the influence of O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, C13H16N6O8) on proliferation and apoptosis in bladder cancer cells and explored possible ROS-related mechanisms. Our results indicated that JS-K could suppress bladder cancer cell proliferation in a concentration- and time-dependent manner and induce apoptosis and ROS accumulation in a concentration-dependent manner...
2015: Scientific Reports
Rui Zhang, Jiyuan Yang, Yan Zhou, Paul J Shami, Jindřich Kopeček
There is a need for new treatment strategies of acute myeloid leukemia (AML). In this study, four different drugs, including cytarabine, daunorubicin, GDC-0980, and JS-K, were investigated in vitro for the two-drug combinations treatment of AML. The results revealed that cytarabine and GDC-0980 had the strongest synergism. In addition, cell cycle analysis was conducted to investigate the effect of the different combinations on cell division. For future in vivo application, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-cytarabine and GDC-0980 conjugates were synthesized, respectively...
January 2016: Macromolecular Bioscience
Cinzia Fionda, Maria Pia Abruzzese, Alessandra Zingoni, Alessandra Soriani, Biancamaria Ricci, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli
BACKGROUND: DNAX accessory molecule-1 (DNAM-1) is an activating receptor constitutively expressed by macrophages/dendritic cells and by T lymphocytes and Natural Killer (NK) cells, having an important role in anticancer responses; in this regard, combination therapies able to enhance the expression of DNAM-1 ligands on tumor cells are of therapeutic interest. In this study, we investigated the effect of different nitric oxide (NO) donors on the expression of the DNAM-1 ligand Poliovirus Receptor/CD155 (PVR/CD155) in multiple myeloma (MM) cells...
2015: BMC Cancer
XiaoHong Wang
SESSION TITLE: Miscellaneous Global Case ReportsSESSION TYPE: Global Case ReportPRESENTED ON: Tuesday, October 28, 2014 at 01:30 PM - 02:30 PMINTRODUCTION: POEMS syndrome is a group of multi-system disease with abnormalities of monoclonal plasma cell. The clinical manifestations of the disease are complex, the system damage is often heterogeneous, and is easy to misdiagnosis. The lung damage of POEMS is rarely mentioned in the literature.CASE PRESENTATION: A 68-year-old man was hospitalized for recurrent cough for 10 years, dyspnea for 7 months...
October 1, 2014: Chest
Imit Kaur, Ken M Kosak, Moises Terrazas, James N Herron, Steven E Kern, Kenneth M Boucher, Paul J Shami
PURPOSE: O(2)-(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] or JS-K is a nitric oxide-producing prodrug of the arylated diazeniumdiolate class with promising anti-tumor activity. JS-K has challenging solubility and stability properties. We aimed to characterize and compare Pluronic(®) P123-formulated JS-K (P123/JS-K) with free JS-K. METHODS: We determined micelle size, shape, and critical micelle concentration of Pluronic(®) P123...
April 2015: Pharmaceutical Research
Rupeng Zhuo, Kenneth M Kosak, Savita Sankar, Elizabeth T Wiles, Ying Sun, Jianxing Zhang, Janet Ayello, Glenn D Prestwich, Paul J Shami, Mitchell S Cairo, Stephen L Lessnick, Wen Luo
Ewing sarcoma is a malignant pediatric bone and soft tissue tumor. Although the 5-year survival rate of localized disease approaches 75%, the prognosis of metastatic and/or therapy-resistant disease remains dismal despite the wide use of aggressive therapeutic strategies. We previously reported that high expression of glutathione S-transferase M4 (GSTM4) in primary tumors correlates with poor patient outcomes. GSTM4 is required for oncogenic transformation and mediates resistance to chemotherapeutic drugs in Ewing sarcoma cells...
2014: Frontiers in Pediatrics
Monika Z Kaczmarek, Ryan J Holland, Stephen A Lavanier, Jami A Troxler, Valentyna I Fesenkova, Charlotte A Hanson, Joan L Cmarik, Joseph E Saavedra, Larry K Keefer, Sandra K Ruscetti
The nitric oxide (NO) prodrug JS-K, a promising anti-cancer agent, consists of a diazeniumdiolate group necessary for the release of NO as well as an arylating ring. In this study, we research the mechanism by which JS-K kills a murine erythroleukemia cell line and determine the roles of NO and arylation in the process. Our studies indicate that JS-K inhibits the PI 3-kinase/Akt and MAP kinase pathways. This correlates with the activation of the tumor suppressor FoxO3a and increased expression of various caspases, leading to apoptosis...
March 2014: Leukemia Research
Anna E Maciag, Ryan J Holland, Y-S Robert Cheng, Luis G Rodriguez, Joseph E Saavedra, Lucy M Anderson, Larry K Keefer
JS-K is a nitric oxide (NO)-releasing prodrug of the O (2)-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models both in vitro and in vivo. The current study of the metabolic actions of JS-K was undertaken to investigate mechanisms of its cytotoxicity. Consistent with model chemical reactions, the activating step in the metabolism of JS-K in the cell is the dearylation of the diazeniumdiolate by glutathione (GSH) via a nucleophilic aromatic substitution reaction...
2013: Redox Biology
Imit Kaur, Moises Terrazas, Ken M Kosak, Steven E Kern, Kenneth M Boucher, Paul J Shami
OBJECTIVE: Nitric oxide (NO) possesses antitumour activity. It induces differentiation and apoptosis in acute myeloid leukaemia (AML) cells. The NO prodrug O(2) -(2,4-dinitrophenyl)1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate, or JS-K, has potent antileukaemic activity. JS-K is also active in vitro and in vivo against multiple myeloma, prostate cancer, non-small-cell lung cancer, glioma and liver cancer. Using the Pluronic P123 polymer, we have developed a micelle formulation for JS-K to increase its solubility and stability...
September 2013: Journal of Pharmacy and Pharmacology
Khosrow Kashfi
Nitric oxide (NO)-releasing agents such as JS-K and NO-releasing hybrids such as NO- and NONO-nonsteroidal anti-inflammatory drugs are novel agents with great potential for controlling cancer. Although studied extensively, a key question pertaining to their molecular targets and mechanism of action remains unclear: the role of NO in the overall biological effect of these agents. It has been shown that NO can directly modify sulfhydryl residues of proteins through S-nitrosylation and induce apoptosis. We showed that 3 structurally diverse NO-nonsteroidal anti-inflammatory drugs S-nitrosylated nuclear factor-κB p65 in vitro and in vivo and also showed that these agents S-nitrosylated caspase-3 in vivo...
2012: Forum on Immunopathological Diseases and Therapeutics
Junjie Fu, Ling Liu, Zhangjian Huang, Yisheng Lai, Hui Ji, Sixun Peng, Jide Tian, Yihua Zhang
A series of hybrids from O(2)-(2,4-dinitrophenyl)diazeniumdiolate and oleanolic acid (OA) were designed, synthesized, and biologically evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione S-transferase π (GSTπ) overexpressed in a number of cancer cells. It was discovered that the most active compound, 21, released high levels of NO selectively in HCC cells but not in the normal cells and exhibited potent antiproliferative activity in vitro as well as remarkable tumor-retarding effects in vivo...
June 13, 2013: Journal of Medicinal Chemistry
Claudia Weidensteiner, Wilfried Reichardt, Paul J Shami, Joseph E Saavedra, Larry K Keefer, Brunhilde Baumer, Anna Werres, Robert Jasinski, Nadja Osterberg, Astrid Weyerbrock
Nitric oxide (NO) released from NO donors can be cytotoxic in tumor cells and can enhance the transport of drugs into brain tumors by altering blood-tumor barrier permeability. The NO donor JS-K [O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] releases NO upon enzymatic activation selectively in cells overexpressing glutathione-S-transferases (GSTs) such as gliomas. Thus, JS-K-dependent NO effects - especially on cell viability and vascular permeability - were investigated in U87 glioma cells in vitro and in an orthotopic U87 xenograft model in vivo by magnetic resonance imaging (MRI)...
April 1, 2013: Nitric Oxide: Biology and Chemistry
Ryan J Holland, Anna E Maciag, Varun Kumar, Lei Shi, Joseph E Saavedra, Robert K Prud'homme, Harinath Chakrapani, Larry K Keefer
Attachment of glutathione (GSH) to cysteine residues in proteins (S-glutathionylation) is a reversible post-translational modification that can profoundly alter protein structure and function. Often serving in a protective role, for example, by temporarily saving protein thiols from irreversible oxidation and inactivation, glutathionylation can be identified and semiquantitatively assessed using anti-GSH antibodies, thought to be specific for recognition of the S-glutathionylation modification. Here, we describe an alternate mechanism of protein glutathionylation in which the sulfur atoms of the GSH and the protein's thiol group are covalently bound via a cross-linking agent, rather than through a disulfide bond...
December 17, 2012: Chemical Research in Toxicology
Rahul S Nandurdikar, Anna E Maciag, Ryan J Holland, Zhao Cao, Paul J Shami, Lucy M Anderson, Larry K Keefer, Joseph E Saavedra
JS-K, a diazeniumdiolate-based nitric oxide (NO)-releasing prodrug, is currently in late pre-clinical development as an anti-cancer drug candidate. This prodrug was designed to be activated by glutathione (GSH) to release NO. To increase the potency of JS-K, we are investigating the effect of slowing the reaction of the prodrugs with GSH. Herein, we report the effect of replacement of nitro group(s) by other electron-withdrawing group(s) in JS-K and its homo-piperazine analogues on GSH activation and the drugs' biological activity...
May 1, 2012: Bioorganic & Medicinal Chemistry
Martin Laschak, Klaus-Dieter Spindler, Andres J Schrader, Andrea Hessenauer, Wolfgang Streicher, Mark Schrader, Marcus V Cronauer
BACKGROUND: Nitric oxide (NO) and its oxidative reaction products have been repeatedly shown to block steroid receptor function via nitrosation of zinc finger structures in the DNA-binding domain (DBD). In consequence NO-donors could be of special interest for the treatment of deregulated androgen receptor(AR)-signaling in castration resistant prostate cancer (CRPC). METHODS: Prostate cancer (PCa) cells were treated with JS-K, a diazeniumdiolate derivate capable of generating large amounts of intracellular NO following activation by glutathione S-transferase...
2012: BMC Cancer
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