Inhibition of nitric oxide-dependent activation of soluble guanylyl cyclase by the antimalarial drug, artemisinin

Severina, I. S.; Pyatakova, N. V.; Bussygina, O G; Михайлицын, Ф. С.; Khropov, Yuri V

doi:10.1016/s0014-2999(02)01266-9

Cited by 6 publications

(3 citation statements)

References 32 publications

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“…In the current investigation, we found that the cytotoxicity of artesunate is associated with inhibition of iNOS. These data are in accord with those of Severina et al [43], who reported that the inhibition of guanylyl cyclase activation by NO donors represents a possible mechanism of the anti-malarial action of artemisinin. Furthermore, artemisinin inhibits the activation of the transcription factor NF-κB and, thereby, nitric oxide synthesis in cytokinestimulated human astrocytoma T67 cells [44].…”

Section: Discussionsupporting

confidence: 93%

Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells

et al. 2008

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Artemisinin is the active principle of the Chinese herb Artemisia annua L. In addition to its anti-malarial activity, artemisinin and its derivatives have been shown to exert profound anti-cancer activity. The endoperoxide moiety in the chemical structure of artemisinin is thought to be responsible for the bioactivity. Here, we analyzed the cytotoxicity and the ability of artemisinin, five of its derivatives, and two other endoperoxides to inhibit generation of nitric oxide (NO). In the RAW 264.7 mouse macrophage cell line, the well-established model cell line to analyze NO generation, artesunate revealed the highest ability to inhibit NO production among all compounds tested. In cytotoxicity assays (XTT assay), the IC(50) value of RAW 264.7 cells for artesunate was determined to be 3.1+/-0.7 microM. In order to associate the cytotoxic effects with specific alteration in gene expression related to NO metabolism and signaling, whole genome mRNA microarray analyses were conducted. RAW 264.7 cells were treated with artesunate using DMSO as vehicle control followed by microarray analysis. A total of 36 genes related to NO metabolism and signaling were found to be differentially expressed upon exposure to artesunate. Apart from NO-related genes, the expression of genes associated with other functional groups was also analyzed. Out of 24 functional groups, differential expression was most prominent in genes involved in cell-to-cell signaling and interactions. Further refinement of this analysis showed that the pathways for cAMP-mediated signaling and Wnt/beta-catenin signaling were most closely related to changes in mRNA expression. In conclusion, NO generation and signaling play a role in exhibiting cytotoxic activity of artesunate. In addition, other signaling pathways also contribute to the inhibitory effect of artesunate towards RAW 264.7 cells pointing to a multi-factorial mode of action of artesunate.

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Section: Discussionsupporting

confidence: 93%

Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells

et al. 2008

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“…В то же время, артемизинин не влияет на активацию фермента протопорфирином IХ, активация которым (в отличие от NO) не связана с гемом [40]. Активность тромбоцитарной гуанилатциклазы в присутствии протопорфирина IX (5 мкМ) без и после добавления артемизинина (10 мкМ) равнялась 371±30 и 393±20 пмоль сGMР/мин/мг белка [41].…”

Section: роль растворимой гуанилатциклазы в действии артемизинина (анunclassified

Soluble guanylate cyclase in the molecular mechanism underlying the therapeutic action of drugs

Pyatakova

Severina

2012

BIOMED KHIM

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The influence of ambroxol - a mucolytic drug - on the activity of human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase and activation of both enzymes by NO-donors (sodium nitroprusside and Sin-1) were investigated. Ambroxol in the concentration range from 0.1 to 10 μM had no effect on the basal activity of both enzymes. Ambroxol inhibited in a concentration-dependent manner the sodium nitroprusside-induced human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase with the IC50 values 3.9 and 2.1 μM, respectively. Ambroxol did not influence the stimulation of both enzymes by protoporphyrin IX.The influence of artemisinin - an antimalarial drug - on human platelet soluble guanylate cyclase activity and the enzyme activation by NO-donors were investigated. Artemisinin (0.1-100 μM) had no effect on the basal activity of the enzyme. Artemisinin inhibited in a concentration-dependent manner the sodium nitroprusside-induced activation of human platelet guanylate cyclase with an IC50 value 5.6 μM. Artemisinin (10 μM) also inhibited (by 71±4.0%) the activation of the enzyme by thiol-dependent NO-donor the derivative of furoxan, 3,4-dicyano-1,2,5-oxadiazolo-2-oxide (10 μM), but did not influence the stimulation of soluble guanylate cyclase by protoporphyrin IX. It was concluded that the sygnalling system NO-soluble guanylate cyclase-cGMP is involved in the molecular mechanism of the therapeutic action of ambroxol and artemisinin.

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“…A variety of other sGC inhibitors, such as N-methylhydroxylamine [93], carnosine [275], streptonigrin [276], artemisinin [277], and ambroxol [278], have been described. No cardiovascular effects of the former that might involve sGC signalling have been reported to date, whereas ambroxol does act as a vasoconstrictor.…”

Section: Soluble Guanylyl Cyclase Inhibitorsmentioning

confidence: 99%

Cardiovascular Effects of Modulators of Soluble Guanylyl Cyclase Activity

Hoenicka

Schmid

2008

CHAMC

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Soluble guanylyl cyclase (sGC) is one of the key enzymes of the nitric-oxide (NO)/cyclic 3',5'-guanosine monophosphate (cGMP) pathway. Located in virtually all mammalian cells, it controls the vessel tone, smooth muscle cell growth, platelet aggregation, and leukocyte adhesion. In vivo sGC activity is mainly regulated by NO which in turn is released from L-arginine by nitric oxide synthases. One of the main diseases of the cardiovascular system, endothelial dysfunction, leads to a diminished NO synthesis and thus increases vessel tone as well as the risk of thrombosis. The predominant therapeutic approach to this condition is a NO replacement therapy, as exemplified by organic nitrates, molsidomin, and other NO releasing substances. Recent advances in drug discovery provided a variety of other approaches to activate sGC, which may help to circumvent both the tolerance problem and some non-specific actions associated with NO donor drugs. Substances like BAY 41-2272 stimulate sGC in a heme-dependent fashion and synergize with NO, allowing to enhance the effects both of endogenous NO and of exogenous NO donors. On the other hand, heme-independent activators like BAY 58-2667 allow to activate sGC even if it is rendered unresponsive to NO due to oxidative stress or heme loss. Furthermore, a few substances have been described as specific inhibitors of sGC that allow to alleviate the effects of excess NO production as seen in septic shock. This review discusses the cardiovascular effects of heme-dependent and heme-independent activators as well as of inhibitors of sGC. Cardiovascular Effects of sGC modulation

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Inhibition of nitric oxide-dependent activation of soluble guanylyl cyclase by the antimalarial drug, artemisinin

Cited by 6 publications

References 32 publications

Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells

Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells

Soluble guanylate cyclase in the molecular mechanism underlying the therapeutic action of drugs

Cardiovascular Effects of Modulators of Soluble Guanylyl Cyclase Activity

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