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Fenghua Kang, Yong Ai, Yihua Zhang, Zhangjian Huang
To search for new drugs for intervention of drug-resistant lung cancer, a series of hybrids 4-15 from 2-cyano-3,12-dioxooleana-9-dien-28-oic acid (CDDO) and O2 -(2,4-dinitrophenyl) diazeniumdiolate were designed, synthesized and biologically evaluated. The most active compound 7 produced relatively high levels of nitric oxide (NO) and reactive oxygen species (ROS) in drug-resistant lung cancer A549/Taxol cells which over-express glutathione S-transferase π (GSTπ), and significantly inhibited the cells' proliferation (IC50  = 0...
February 23, 2018: European Journal of Medicinal Chemistry
Zhangjian Huang, Jianbing Wu, Yu Zou, Haoliang Yuan, Yinqiu Zhang, Yue Fei, Atul Bhardwaj, Jatinder Kaur, Edward E Knaus, Yihua Zhang
A group of glutathione S-transferase π (GSTπ)-activatable O2-(sulfonylethyl derived)diazeniumdiolates 5-12 were designed and synthesized. These compounds could be activated by GSTπ to initiate the β-elimination reaction, liberating an active vinyl sulfone-based GSH derivative and a diazeniumdiolate anion which subsequently releases NO in situ. The most active compound 6 released relatively high levels of NO and inhibited proliferation of melanoma B16 cells, superior to a diazeniumdiolate-based anticancer agent JS-K (1)...
February 8, 2018: Journal of Medicinal Chemistry
Qixing Li, Pian Zou, Jianbo Sun, Li Chen
A series of O2 -(2,4-dinitrophenyl)diazeniumdiolates derivatives were designed, synthesized and antiproliferative activities evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione S-transferases π (GSTπ). Most of these derivatives exhibited significant antiproliferative activities compared to the reported NO-donor prodrug JS-K, among which compounds 27 and 36 had superior potency with IC50 below 1 μM. NO released amounts detection of all derivatives indicated that the antiproliferative activities were positively correlated with the levels of intracellular NO release in HCT116 cells...
January 1, 2018: European Journal of Medicinal Chemistry
Max Heckler, Nadja Osterberg, Jessica Guenzle, Nina Kristin Thiede-Stan, Wilfried Reichardt, Claudia Weidensteiner, Joseph E Saavedra, Astrid Weyerbrock
As a potent radiosensitizer nitric oxide (NO) may be a putative adjuvant in the treatment of malignant gliomas which are known for their radio- and chemoresistance. The NO donor prodrug JS-K (O2-(2.4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1,2-diolate) allows cell-type specific intracellular NO release via enzymatic activation by glutathione-S-transferases overexpressed in glioblastoma multiforme. The cytotoxic and radiosensitizing efficacy of JS-K was assessed in U87 glioma cells in vitro focusing on cell proliferation, induction of DNA damage, and cell death...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Mingning Qiu, Longzhi Ke, Sai Zhang, Xin Zeng, Zesong Fang, Jianjun Liu
PURPOSE: Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells. METHODS: The effect of JS-K on anti-cancer activity of Doxorubicin was investigated in renal carcinoma cells via detecting cell proliferation, cytotoxicity, cell death and apoptosis and expressions of apoptotic-related proteins...
August 2017: Cancer Chemotherapy and Pharmacology
Zhengyun Liu, Guangmin Li, Ying Gou, Dongyan Xiao, Guo Luo, Joseph E Saavedra, Jie Liu, Huan Wang
Hepatocellular carcinoma (HCC) is the most important cause of cancer-related death, and 85% of HCC is caused by chronic HBV infection, the prognosis of patients and the reduction of HBV DNA levels remain unsatisfactory. JS-K, a nitric oxide-releasing diazeniumdiolates, is effective against various tumors, but little is known on its effects on HBV positive HCC. We found that JS-K reduced the expression of HBsAg and HBeAg in HBV-positive HepG2.2.15 cells. This study aimed to further examine anti-tumor effects of JS-K on HepG2...
August 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Guobin Tan, Mingning Qiu, Lieqian Chen, Sai Zhang, Longzhi Ke, Jianjun Liu
BACKGROUND: In view of the fact that JS-K might regulate ubiquitin E3 ligase and that ubiquitin E3 ligase plays an important role in the mechanism of CRPC formation, the goal was to investigate the probable mechanism by which JS-K regulates prostate cancer cells. METHODS: Proliferation inhibition by JS-K on prostate cancer cells was examined usingCCK-8 assays. Caspase 3/7 activity assays and flow cytometry were performed to examine whether JS-K induced apoptosis in prostate cancer cells...
May 26, 2017: BMC Cancer
Mingning Qiu, Lieqian Chen, Guobin Tan, Longzhi Ke, Sai Zhang, Hege Chen, Jianjun Liu
Reactive oxygen species (ROS) are chemical species that alter redox status, and are responsible for inducing carcinogenesis. The purpose of the present study was to assess the effects of the glutathione S transferase-activated nitric oxide donor prodrug, JS-K, on ROS accumulation and on proliferation and apoptosis in human prostate cancer cells. Cell proliferation and apoptosis, ROS accumulation and the activation of the mitochondrial signaling pathway were measured. The results demonstrated that JS-K may inhibit prostate cancer cell growth in a dose- and time-dependent manner, and induce ROS accumulation and apoptosis in a dose-dependent manner...
March 2017: Oncology Letters
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
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