Inhibition of benzo(a)pyrene-induced forestomach carcinogenesis in mice by thymoquinone

Badary, Osama A.; Al‐Shabanah, Othman A.; Nagi, Mahmoud N.; Al-Rikabi, Ammar C.; Elmazar, Mohamed M.

doi:10.1097/00008469-199910000-00009

Cited by 145 publications

(90 citation statements)

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“…TQ has also been reported to enhance antitumor activity of ifosfamide in Ehrlich ascites carcinoma -bearing mice (8), prevent cisplatin-induced nephrotoxicity in mice and rats (19), ameliorate benzo(a)pyrene-induced forestomach carcinogenesis (20), inhibit cyclooxygenase 2 (COX-2) expression and prostaglandin production in a mouse model of allergic airway inflammation (21), and protect against doxorubicin-induced cardiotoxicity in mice (22). How TQ manifests these activities is not fully understood, but it has been shown to down-regulate the expression of Bcl-x L (11), COX-2 (21), iNOS (23), 5-lipooxygenase (24), TNF (25), and cyclin D1 (26), all known to be regulated by nuclear factor-nB (NF-nB).…”

Section: Introductionmentioning

confidence: 99%

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

Sethi

Ahn

Aggarwal

2008

Molecular Cancer Research

300

218

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Thymoquinone (TQ), derived from the medicinal plant Nigella sativa, exhibits antiinflammatory and anticancer activities through mechanism(s) that is not fully understood. Because numerous effects modulated by TQ can be linked to interference with the nuclear factor-KB (NF-KB) signaling, we investigated in detail the effect of this quinone on NF-KB pathway. As examined by DNA binding, we found that TQ suppressed tumor necrosis factor -induced NF-KB activation in a dose-and time-dependent manner and inhibited NF-KB activation induced by various carcinogens and inflammatory stimuli. The suppression of NF-KB activation correlated with sequential inhibition of the activation of IKBA kinase, IKBA phosphorylation, IKBA degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-KB -dependent reporter gene expression. TQ specifically suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by DTT. However, TQ did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine residue 38 mutated to serine. TQ also down-regulated the expression of NF-KB -regulated antiapoptotic (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, and survivin), proliferative (cyclin D1, cyclooxygenase-2, and c-Myc), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by tumor necrosis factor and chemotherapeutic agents. Overall, our results indicate that the anticancer and antiinflammatory activities previously assigned to TQ may be mediated in part through the suppression of the NF-KB activation pathway, as shown here, and thus may have potential in treatment of myeloid leukemia and other cancers.

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Section: Introductionmentioning

confidence: 99%

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

Sethi

Ahn

Aggarwal

2008

Molecular Cancer Research

300

218

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“…In the hepatoprotection studies, finely powdered TQ was suspended in water along with valproate or alone in a concentration of 0.025% w/v. The daily dose intake was calculated to be in the range of 5-5.5 mg/kg/day that has already been reported in the literature [16] and the treatment continued for the same duration as for valproate.…”

Section: Assessment Of the Thymoquinone (Tq)-hepatoprotective Activitmentioning

confidence: 99%

“…Thymoquinone pretreatment in drinking water for five days (8 mg/ kg /day) protected organs against oxidative damage induced by a variety of free radical generating agents including doxorubicin [13], cisplatin [14] and CCl 4 [15]. Badary et al, [16] administered TQ in drinking water to rats (5 mg/kg/day) for 5 days before and after ifosfamide (IFO), a cytotoxic agent. This treatment ameliorated the severity of IFO-induced renal damage.…”

Section: Introductionmentioning

confidence: 99%

Beneficial Interaction of Thymoquinone and Sodium Valproate in Experimental Models of Epilepsy: Reduction in Hepatotoxicity of Valproate

et al. 2006

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The antiepileptic potential of thymoquinone (TQ) was studied in mice by using pentylenetetrazole (PTZ) and maximal electroshock seizure (MES)-induced convulsion models. In this investigation, the combined treatment of TQ and sodium valproate (SVP) was also studied. The aim of this part was to minimize SVPinduced hepatotoxic implications, by reducing its antiepileptic dose. TQ in both PTZ-and MES-models increased SVP potency. The experiments dealing with the effects of TQ on the ED 50 of SVP revealed that TQ reduced the ED 50 of SVP in both the models. However, this potentiation of SVP antiepileptic response was relatively more significant in PTZ model at both 50 and 100 mg/kg doses of TQ. Although very well tolerated and effective, SVP is well known for its hapatotoxic implications. In the experiment dealing with subacute treatment, SVP (1300-1500mg/kg/day in drinking water) for 21 days, produced hepatotoxicity in mice, characterized by elevated serum ALT and AST, reduced levels of non protein sulfhydryls and increase in lipid peroxidation in hepatic cells. Hepato-protection was successfully achieved when TQ (5-5.5mg/kg/day) was combined with SVP in drinking water for the same duration. The protective activity of TQ was evident by averting any serum ALT rise seen in SVP treatment. Though there is no prevention to the rise in lipid peroxidation in hepatic tissue but the same time a significant recovery in glutathione was evident by TQ joint treatment.However, a combination of TQ and low dose of SVP may be useful strategy to minimize adverse reactions of SVP. From the results of the present study that disclosed a protective role of TQ against SVP toxic damage to the liver, it could be harmful effects. It also protected against the liver enzyme induction seen in the case of SVP alone. KeywordsThymoquinone, valproate, potentiation, maximal electroshock convulsions, hepatoprotection.Abbreviations: maximal electroshock seizure = MES; pentylenetetrazole = PTZ; thymoquinone = TQ; sodium valproate = SVP; malondialdehyde = MDA; nonprotein sulfhydryl groups = NPSH; glutathione = G-SH.

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“…The inhibitory effects of TQ on chemically induced carcinogenesis have been also recognized. For example, TQ inhibited 20-methylcholantherene-induced fibrosarcoma, 9 benzo[a]pyrene-induced forestomach carcinogenesis 10 and tumor formation in DMBA-initiated, TPA-promoted mouse skin. 5 Additionally, a potential role has been reported for TQ as a chemopreventive agent at the early stage of skin tumorigenesis.…”

mentioning

confidence: 99%

Thymoquinone induces apoptosis through activation of caspase‐8 and mitochondrial events in p53‐null myeloblastic leukemia HL‐60 cells

El‐Mahdy

Zhu

Wang

et al. 2005

Intl Journal of Cancer

244

158

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Thymoquinone (TQ), the major biologically active component isolated from a traditional medicinal herb, Nigella sativa Linn, is a potential chemopreventive and chemotherapeutic compound. Despite the promising antineoplastic activities of TQ, the molecular mechanism of its pharmacologic effects is poorly understood. Here, we report that TQ exhibits antiproliferative effect, induces apoptosis, disrupts mitochondrial membrane potential and triggers the activation of caspases 8, 9 and 3 in myeloblastic leukemia HL-60 cells. The apoptosis induced by TQ was inhibited by a general caspase inhibitor, z-VAD-FMK; a caspase-3-specific inhibitor, z-DEVD-FMK; as well as a caspase-8-specific inhibitor, z-IETD-FMK. Moreover, the caspase-8 inhibitor blocked the TQ-induced activation of caspase-3, PARP cleavage and the release of cytochrome c from mitochondria into the cytoplasm. In addition, TQ treatment of HL-60 cells caused a marked increase in Bax/Bcl2 ratios due to upregulation of Bax and downregulation of Bcl2 proteins. These results indicate that TQ-induced apoptosis is associated with the activation of caspases 8, 9 and 3, with caspase-8 acting as an upstream activator. Activated caspase-8 initiates the release of cytochrome c during TQ-induced apoptosis. Overall, these results offer a potential mechanism for TQ-induced apoptosis in p53-null HL-60 cancer cells. ' 2005 Wiley-Liss, Inc.

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Inhibition of benzo(a)pyrene-induced forestomach carcinogenesis in mice by thymoquinone

Cited by 145 publications

References 0 publications

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

Beneficial Interaction of Thymoquinone and Sodium Valproate in Experimental Models of Epilepsy: Reduction in Hepatotoxicity of Valproate

Thymoquinone induces apoptosis through activation of caspase‐8 and mitochondrial events in p53‐null myeloblastic leukemia HL‐60 cells

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