Effect of Quinacrine, a Phospholipase A&lt;sub&gt;2&lt;/sub&gt; Inhibitor on Stress and Chemically Induced Gastroduodenal Ulcers

Moutaery, Ahmed R. Al; Tariq, Mohammad

doi:10.1159/000201435

Cited by 15 publications

(6 citation statements)

References 25 publications

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“…7). Previous studies have suggested inhibition of phospholipase A2 as an inhibitory mechanism of QC in inflammation 32. It is worth noting that the inhibition of phospholipase A2 actually increases rather than decreases CHS responses 33, which in light of the current results argues against inhibition of this enzyme as a mechanism of QC‐mediated suppression of CHS responses.…”

Section: Discussionsupporting

confidence: 57%

Quinacrine inhibits the epidermal dendritic cell migration initiating T cell‐mediated skin inflammation

et al. 2007

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Quinacrine (QC) is an anti-inflammatory drug that has been used for the treatment of malaria and rheumatoid diseases. The mechanism(s) underlying the anti-inflammatory activity of QC remains poorly understood. We recently reported the QC-mediated inhibition of the NF-jB pathway using an in vitro model. To test this potential mechanism in vivo, we used the contact hypersensitivity response (CHS) to chemical allergen sensitization and challenge in mice as a model of skin inflammation. The results indicated that QC treatment inhibited NF-jB activation in the skin during allergen sensitization. This inhibition was reflected by decreased mRNA expression and protein production of the NF-jB-dependent cytokines TNF-a and IL-1b and the chemokine CCL21 in the skin. The decreases in these cytokines resulted in reduced migration of allergen-presenting dendritic cells from the skin into skin-draining lymph nodes and markedly decreased activation of effector CD8 + T cells for the CHS response to allergen challenge (inhibitory concentration 50% or IC 50 was 55 mg/kg). These findings reveal a previously unrecognized mechanism of QC-mediated inhibition of inflammation.

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Section: Discussionsupporting

confidence: 57%

Quinacrine inhibits the epidermal dendritic cell migration initiating T cell‐mediated skin inflammation

et al. 2007

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“…Thus, 9AA and QC act by converting NF-B to a transcriptionally inactive state that becomes trapped in the nucleus. This mechanism seems to be more relevant to antiinflammatory properties of QC, which was used previously to treat rheumatoid disease, than the inhibition of phospholipase A2 (PLA2), traditionally considered to be the QC target (21). It is noteworthy that other PLA2 inhibitors we tested (thioetheramide-PC, arachidonyl trifluoromethyl ketone, and others) could neither induce p53 nor inhibit NF-B (data not shown).…”

Section: Aa and Qc Represent A Previously Uncharacterized Type Of Nf-bmentioning

confidence: 89%

Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-κB-dependent mechanism of p53 suppression in tumors

Gurova

Hill

Guo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

249

266

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Renal cell carcinomas (RCC) commonly retain wild-type but functionally inactive p53, which is repressed by an unknown dominant mechanism. To help reveal this mechanism, we screened a diverse chemical library for small molecules capable of restoring p53-dependent transactivation in RCC cells carrying a p53-responsive reporter. Among the compounds isolated were derivatives of 9-aminoacridine (9AA), including the antimalaria drug quinacrine, which strongly induced p53 function in RCC and other types of cancer cells. Induction of p53 by these compounds does not involve genotoxic stress and is mediated by suppression of NF-B activity. In contrast to agents that target I B kinase 2, 9AA and quinacrine can effectively suppress both basal and inducible activities of NF-B, representing inhibitors of a previously undescribed type that convert NF-B from a transactivator into a transrepressor, leading to accumulation of inactive nuclear complexes with unphosphorylated Ser-536 in the p65͞RelA subunit. p53 function in RCC can be restored by ectopic expression of a superrepressor of I B as effectively as by 9AA-derived compounds. These findings suggest that the complete or partial repression of p53 observed in many tumors can be the result of constitutive activation of NF-B. The results demonstrate, in principle, the possibility to kill cancer cells selectively through simultaneous inhibition of NF-B and activation of p53 by a single small molecule and suggest anticancer applications for the well known antimalaria drug quinacrine.anticancer treatment ͉ apoptosis ͉ chemical library ͉ quinacrine T he protein p53 controls genetic stability and reduces the risk of cancer through induction of growth arrest or apoptosis in response to DNA damage or deregulation of proto-oncogenes (1). The efficacy of p53 as a tumor-preventing factor is reflected by the high frequency of p53 loss, in at least 50% of human tumors, due to inactivating mutations (2). Understanding the mechanisms of functional inactivation of wild-type p53 in human tumors, for example, by overexpression of natural antagonists of p53, Mdm2, or the viral protein E6, helps to define prospective targets for treating cancer by restoring p53 function (3).We have recently shown that renal cell carcinomas (RCC), the most frequent and least curable type of kidney cancer, maintain wild-type but functionally inactive p53 (4). The mechanism of p53 repression in RCC is dominant, and therefore ''druggable,'' and different from that of all reported cases of p53 repression in tumors, suggesting the existence of an as-yet-unknown molecular target for restoring p53 function in cancer. As an approach to finding such factor(s), we have isolated a set of compounds that can restore p53 function in RCC and strongly activate p53 in many other types of cancer cells. Among the most effective compounds from this set were derivatives of 9-aminoacridine (9AA), including an old-known antimalaria drug quinacrine (QC). Analysis of the molecular mechanisms of action of 9AA and QC showed that p53 activat...

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“…1 & Table 4 ). Our earlier studies showed highly significant protective effect of quinacrine against cyclosporine induced renal toxicity [ 34 ], ethanol induced gastric mucosal injury [ 35 ] and1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neuronal injury [ 36 ]. Quinacrine has also been shown to exert significant protective effect against ischemia induced myocardial [ 37 ] and cerebral [ 38 , 39 ] injury.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of quinacrine against glycerol-induced acute kidney injury in rats

et al. 2017

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BackgroundAcute kidney injury (AKI) is a serious clinical problem with high rate of mortality and morbidity. Currently used prophylactic and therapeutic strategies to address AKI are limited and warrant further studies. In the present study an attempt was made to investigate the effect of quinacrine, a phospholipase A2 inhibitor against glycerol induced AKI in rats.MethodsAdult female Wistar rats were divided in to five groups. After 24 h of water deprivation rats in groups 3, 4 and 5 received an intraperitoneal injection of quinacrine (3 mg/kg, 10 mg/kg and 30 mg/kg of body weight respectively). Thirty minutes after the first injection of quinacrine animals in groups 3, 4 and 5 received an intramuscular injection of 25% glycerol (10 ml/kg of body weight). The animals in group 2 received 25% glycerol (10 ml/kg of body weight) only whereas rats in group 1 served as control . The quinacrine administration was continued once daily for three days, on the fourth day animals were sacrificed, blood and kidney were collected for various biochemical and histopathological studies.ResultsGlycerol treatment produced significant renal structural abnormalities and functional impairment (increased urea and creatinine). Increase in myeloperoxidase (MPO) and malondialdehyde (MDA) clearly suggested the involvement of oxidative stress and neutrophilic activity following glycerol administration. Quinacrine dose dependently attenuated glycerol induced structural and functional changes in kidney.ConclusionThe reversal of glycerol induced AKI by quinacrine points towards a role of phospholipase A2 (PLA2) in the pathogenesis of renal injury. The result of this study suggests that quinacrine may offer an alternative mode of treatment for AKI.

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Effect of Quinacrine, a Phospholipase A<sub>2</sub> Inhibitor on Stress and Chemically Induced Gastroduodenal Ulcers

Cited by 15 publications

References 25 publications

Quinacrine inhibits the epidermal dendritic cell migration initiating T cell‐mediated skin inflammation

Quinacrine inhibits the epidermal dendritic cell migration initiating T cell‐mediated skin inflammation

Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-κB-dependent mechanism of p53 suppression in tumors

Protective effect of quinacrine against glycerol-induced acute kidney injury in rats

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