The Nitric Oxide Prodrug JS-K Is Effective against Non–Small-Cell Lung Cancer Cells In Vitro and In Vivo: Involvement of Reactive Oxygen Species

Maciąg, Anna; Chakrapani, Harinath; Saavedra, Joseph E.; Morris, Nicole; Holland, Ryan J.; Kosak, Ken M.; Shami, Paul J.; Anderson, Lucy M.; Keefer, Larry K.

doi:10.1124/jpet.110.174904

Cited by 64 publications

(75 citation statements)

References 38 publications

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“…Trx expression in these tumors is commonly associated with high proliferation index and inversely correlates with apoptosis [52, 53]. Of further note, it was shown that A549 cells display enhanced TrxR activity and high resistance to nitrosative stress [54, 55]. These previous observations together with the present study suggest the possibility that elevated activity of Trx/TrxR could promote lung cancer progression through their denitrosylase activity.…”

Section: Discussionsupporting

confidence: 74%

Nitrosothiol-Trapping-Based Proteomic Analysis of S-Nitrosylation in Human Lung Carcinoma Cells

et al. 2017

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Nitrosylation of cysteines residues (S-nitrosylation) mediates many of the cellular effects of nitric oxide in normal and diseased cells. Recent research indicates that S-nitrosylation of certain proteins could play a role in tumor progression and responsiveness to therapy. However, the protein targets of S-nitrosylation in cancer cells remain largely unidentified. In this study, we used our recently developed nitrosothiol trapping approach to explore the nitrosoproteome of human A549 lung carcinoma cells treated with S-nitrosocysteine or pro-inflammatory cytokines. Using this approach, we identified about 300 putative nitrosylation targets in S-nitrosocysteine-treated A549 cells and approximately 400 targets in cytokine-stimulated cells. Among the more than 500 proteins identified in the two screens, the majority represent novel targets of S-nitrosylation, as revealed by comparison with publicly available nitrosoproteomic data. By coupling the trapping procedure with differential thiol labeling, we identified nearly 300 potential nitrosylation sites in about 150 proteins. The proteomic results were validated for several proteins by an independent approach. Bioinformatic analysis highlighted important cellular pathways that are targeted by S-nitrosylation, notably, cell cycle and inflammatory signaling. Taken together, our results identify new molecular targets of nitric oxide in lung cancer cells and suggest that S-nitrosylation may regulate signaling pathways that are critically involved in lung cancer progression.

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Section: Discussionsupporting

confidence: 74%

Nitrosothiol-Trapping-Based Proteomic Analysis of S-Nitrosylation in Human Lung Carcinoma Cells

et al. 2017

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“…While significant progress has been made in the last decade, the role of * NO/ * NO-related species remains poorly understood in chemotherapy and drug resistance. Here, we review the role of * NO/ S-nitrosothiols (sugar-SNAP) that resulted from enhanced uptake of saccharides in tumor cells and delivering * NO directly to tumor cells (34). Reynolds et al [29] have reported synthesis of polysaccharidebased dextran thiomers which contained covalently attached NOdonors.…”

Section: +mentioning

confidence: 99%

“…JS-K is active against human non-small cell lung cancer cells [34] and induces apoptosis in human multiple myeloma cells both in vitro and in vivo [35]. It was found that JS-K was activated following reactions with glutathione to produce * NO in vivo catalyzed by glutathione S-transferase [33].…”

Section: Becausementioning

confidence: 99%

Nitric Oxide: Friend or Foe in Cancer Chemotherapy and Drug Resistance: A Perspective

Sinha

2016

J Cancer Sci Ther

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A successful treatment of cancers in the clinic has been difficult to achieve because of the emergence of drug resistant tumor cells. While various approaches have been tried to overcome multi-drug resistance, it has remained a major road block in achieving complete success in the clinic. Extensive research has identified various mechanisms, including overexpression of P-glycoprotein 170, modifications in activating or detoxification enzymes (phase I and II enzymes), and mutation and/or decreases in target enzymes in cancer cells. However, nitric oxide and/or nitric oxide-related species have not been considered an important player in cancer treatment and or drug resistance. Here, we examine the significance of nitric oxide in the treatment and resistance mechanisms of various anticancer drugs. Furthermore, we describe the significance of recently reported effects of nitric oxide on topoisomerases and the development of resistance to topoisomerase-poisons in tumor cells.Nitric oxide is also implicated in cancer cell killing, cancer progression and metastasis and poor survival [13][14][15][16][17]. A poor clinical outcome is believed to result from * NO-induced rapid tumor growth, resulting in hypoxia, nutrient deprivation, poor drug delivery, and selection for drug-resistant tumor cells. In vivo, * NO is formed from L-arginine by nitric oxide synthase (NOS). Three forms of NOS have been identified, including neuronal (nNOS), endothelial (eNOS), and a Ca 2+ -independent inducible isoform (iNOS). High expression of iNOS and increased production of • NO have been described in many human tumors, including breast, prostate and colorectal cancers [17][18][19][20]. Increased and continuous generation of * NO plays a significant role in the regulation of cancer cell progression and carcinogenesis. Hibbs et al. [21,22] and Stuehr and Nathan [23] have shown that co-culturing of leukemia L1210 cells with activated peritoneal macrophages results in the inhibition of L1210 cell proliferation which is correlated with nitrite formation. Inhibitors of NOS (L-NAME) and myoglobin, a scavenger of * NO 2 were effective in inhibiting cell killing actions of the activated macrophages, suggesting that * NO is responsible for the killing actions of activated macrophages towards cancer cells.It is believed that DNA damage and apoptosis induced by * NO in tumor cells cause tumor cell death; studies are needed to explore processes to deliver the highest concentrations of * NO in tumor cells using NO-donors as single chemotherapeutic agents or in combination with other chemotherapeutic agents. While significant progress has been made in the last decade, the role of * NO/ * NO-related species remains poorly understood in chemotherapy and drug resistance. Here, we review the role of * NO/ * NO-related species in cancer chemotherapy

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“…O 2 -(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] or JS-K (Figure 1), an arylated diazeniumdiolate has potent anti-leukemic activity in vitro and in vivo (10). In in vivo murine models, JS-K was also found to be effective against prostate cancer (10), hepatoma (11), multiple myeloma (12) and non-small cell lung cancer (13). JS-K also possesses anti-angiogenic activity both in vitro and in vivo (14).…”

Section: Introductionmentioning

confidence: 99%

Effect of a Pluronic® P123 Formulation on the Nitric Oxide-Generating Drug JS-K

et al. 2014

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Purpose O2-(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. Efficacy was evaluated in vitro using HL-60 and U937 cells and in vivo in a xenog raft in NOD/SCID IL2Rγnull mice using HL-60 cells. We compared JS-K and P123/JS-K stability in different media. We also compared plasma protein binding of JS-K and P123/JS-K. We determined the binding and Stern Volmer constants, and thermodynamic parameters. Results Spherical P123/JS-K micelles were smaller than blank P123. P123/JS-K formulation was more stable in buffered saline, whole blood, plasma and RPMI media as compared to free JS-K. P123 affected the protein binding properties of JS-K. In vitro it was as efficacious as JS-K alone when tested in HL-60 and U937 cells and in vivo greater tumor regression was observed for P123/JS-K treated NOD/SCID IL2Rγnull mice when compared to free JS-K-treated NOD/SCID IL2Rγnull mice. Conclusions Pluronic® P123 solubilizes, stabilizes and affects the protein binding characteristics of JS-K. P123/JS-K showed more in vivo anti-tumor activity than free JS-K.

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The Nitric Oxide Prodrug JS-K Is Effective against Non–Small-Cell Lung Cancer Cells In Vitro and In Vivo: Involvement of Reactive Oxygen Species

Cited by 64 publications

References 38 publications

Nitrosothiol-Trapping-Based Proteomic Analysis of S-Nitrosylation in Human Lung Carcinoma Cells

Nitrosothiol-Trapping-Based Proteomic Analysis of S-Nitrosylation in Human Lung Carcinoma Cells

Nitric Oxide: Friend or Foe in Cancer Chemotherapy and Drug Resistance: A Perspective

Effect of a Pluronic® P123 Formulation on the Nitric Oxide-Generating Drug JS-K

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