The nitric oxide prodrug, V-PYRRO/NO, mitigates arsenic-induced liver cell toxicity and apoptosis

Qu, Wei; Liu, Jie; Fuquay, Richard; Saavedra, Joseph E.; Keefer, Larry K.; Waalkes, Michael P.

doi:10.1016/j.canlet.2007.06.009

Cited by 9 publications

(12 citation statements)

References 32 publications

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“…Recently, activation of c-jun N-terminal kinase (NJK) pathway has been found critical to As-induced apoptosis in cultured rat liver cells [30]. Expression profiles of a number of signaling pathways were studied in the lung of mice offered arsenic in drinking water for 5 weeks [31].…”

Section: Apoptosismentioning

confidence: 99%

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Metals and apoptosis: Recent developments

Rana

2008

Journal of Trace Elements in Medicine and Biology

333

175

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Section: Apoptosismentioning

confidence: 99%

“…Intracellular Ca disturbances, PKC activation [12]. Activation of c-jun -N-terminal kinase (NJK) pathway [30].…”

Section: Article In Pressmentioning

confidence: 99%

Metals and apoptosis: Recent developments

Rana

2008

Journal of Trace Elements in Medicine and Biology

333

175

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“…In this regard, V‐PYRRO/NO pretreatment greatly enhances arsenic induction of MT probably as part of its mechanism in reducing arsenic toxicity. ( 11 ) NO released from NO‐donating compounds increases MT levels, at least indirectly. ( 20 )…”

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confidence: 99%

“…( 21 ) The levels of phosphorylated JNK1/2 and JNK kinase activity are markedly decreased in cells chronically exposed to arsenic. ( 21 ) Activation of the JNK pathway can be critical to apoptosis and pretreatment with V‐PYRRO/NO suppresses arsenic‐induced JNK activation in liver cells, ( 11 ) indicating that NO has the capacity to alter the adverse effects of arsenic with regard to apoptotic signaling.…”

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confidence: 99%

V‐PROLI/NO, a nitric oxide donor prodrug, protects liver cells from arsenic‐induced toxicity

Qu¹,

Liu²,

Dill³

et al. 2009

Cancer Science

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(1,2) In particular, arsenic trioxide treatment has proven to be curative of acute promyelocytic leukemia (APL) and markedly improves the clinical outcome of even refractory or relapsed APL.(3) Arsenicals are now being tested against a variety of other tumors, including solid tumors.(4) However, arsenicals can be quite toxic and concern about serious side-effects has been raised, such as the potential for fatal hepatotoxicity in patients undergoing arsenical chemotherapy for cancer.(5) The liver is a major organ for arsenic toxicity and metabolism.(6) Individual variation in susceptibility to arsenicinduced toxicity clearly occurs and is probably related to genetic polymorphisms associated with altered capacity for methylation of inorganic arsenic.(5) Thus, adjuvant pharmacological agents that effectively and specifically limit arsenical hepatotoxicity could potentially increase arsenical therapeutic utility.Nitric oxide (NO) is a signaling mediator produced by cells involved in numerous critical functions.(7) Recently, several novel NO-donating compounds have shown promising features related to their pharmacological use in cancer chemotherapy. Indeed, the production of site-specific and/or novel NO-donating agents is an important trend in the development of agents with therapeutic and chemo-preventive potential.(8) For instance, our work indicates that O 2 -vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2 diolate (V-PYRRO/NO) mitigates the hepatotoxicity of various compounds both in vivo and in vitro, including the potentially hepatotoxic chemotherapeutic metalloid, arsenic. is structurally similar to V-PYRRO/NO, but has an additional carboxylic acid and appears to have liver specificity, as it is metabolized to release NO by cytochrome P450, (12) the most important of which appears to be CYP2E1.(13) The major limiting effects of arsenical chemotherapy would be hepatotoxicity. (14) However, whether V-PROLI/NO is protective against arsenic toxicity in liver or liver cells has not been defined.Metallothionein (MT) is a small, soluble, cysteine-rich, metalbinding protein that helps detoxicate various metals and metalloids.(15) In fact, a recent study showed that human populations poorly expressing MT may be more sensitive to chronic arsenic intoxication.(16) Furthermore, arsenic induces MT expression both in vitro and in vivo, (17)(18)(19) and arsenic or its methylated metabolites interacted with MT in a stoichiometric fashion. (17) Taken together, these data suggest that MT can decrease arsenic toxicity. In this regard, V-PYRRO/NO pretreatment greatly enhances arsenic induction of MT probably as part of its mechanism in reducing arsenic toxicity.(11) NO released from NOdonating compounds increases MT levels, at least indirectly. (20) Mitogen-activated protein kinases (MAPK) are a family of serine/threonine phosphorylating proteins which can mediate signal transduction pathways from a variety of extracellular signals to regulate the expression of specific genes. The major MAPK, the extracellular signal-regulated kinases ...

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“…Many NO donor prodrugs have been designed with pharmacological potential [9]. Indeed, our prior work indicates that O 2 -vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), a liver-selective NO-releasing agent metabolized by human CYP450 [26], mitigates the toxicity of various compounds in liver cells both in vivo and in vitro , including arsenic [27,28]. V-PROLI/NO is a relatively new NO donor prodrug whose CYP450-induced NO-donating metabolite PROLI/NO has vasodilatory and antithrombotic effects [29-31].…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide donor, V-PROLI/NO, provides protection against arsenical induced toxicity in rat liver cells: Requirement for Cyp1a1

Cheng

Dill

et al. 2011

Chemico-Biological Interactions

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Arsenic is a cancer chemotherapeutic but hepatotoxicity can be a limiting side effect. O2-Vinyl 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (V-PROLI/NO) is a nitric oxide (NO) donor prodrug and metabolized by liver cytochromes P450 (CYP450) to release NO. The effects of V-PROLI/NO pretreatment on the toxicity of arsenic (as NaAsO2) were studied in a rat liver cell line (TRL 1215). The cells acted upon the prodrug to release NO, as assessed by nitrite levels, in a time-dependent fashion to maximal levels of 8-fold above basal levels. Pretreatment with V-PROLI/NO markedly reduced arsenic cytolethality which was directly related to the level of NO produced by V-PROLI/NO treatment. Cyp1a1 expression was directly related to the level of NO production and to reduced arsenic cytotoxicity. V-PROLI/NO pretreatment markedly reduced arsenic-induced apoptosis and suppressed phosphorylation of JNK1/2. V-PROLI/NO pretreatment facilitated additional increases in arsenic-induced metallothionein, a metal-binding protein important in arsenic tolerance. Thus, V-PROLI/NO protects against arsenic toxicity in rat liver cells, reducing cytolethality, apoptosis and dysregulation of MAPKs, through generation of NO formed after metabolism by liver cell enzymes, possibly including Cyp1a1. CYP450 required for NO production from V-PROLI/NO treatment in the rat and human appears to differ as we have previously studied the ability of V-PROLI/NO to prevent arsenic toxicity in human liver cells where it reduced toxicity apparently through a CYP2E1-mediated metabolic mechanism. None-the-less, it appears that both rat and human liver cells act upon V-PROLI/NO via a CYP450-related mechanism to produce NO and subsequently reduce arsenic toxicity.

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The nitric oxide prodrug, V-PYRRO/NO, mitigates arsenic-induced liver cell toxicity and apoptosis

Cited by 9 publications

References 32 publications

Metals and apoptosis: Recent developments

Metals and apoptosis: Recent developments

V‐PROLI/NO, a nitric oxide donor prodrug, protects liver cells from arsenic‐induced toxicity

Nitric oxide donor, V-PROLI/NO, provides protection against arsenical induced toxicity in rat liver cells: Requirement for Cyp1a1

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