In vitro inhibition of growth and induction of apoptosis in cancer cell lines by thymoquinone

Shoieb, Ahmed; Elgayyar, Mona; Dudrick, Paul S.; Bell, John L.; Tithof, Patricia K.

doi:10.3892/ijo.22.1.107

Cited by 150 publications

(174 citation statements)

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“…It is possible that suppression of various other tumor cell lines previously reported (7,(10)(11)(12)(13)(14) is also through antiapoptotic and proliferative gene products, as described here. In animal models, TQ has been shown to suppress acetic acid -induced colitis in rats (16), inhibit TNF production in murine septic peritonitis (17), and reduce carrageenan-induced paw edema in rats (18).…”

Section: Discussionmentioning

confidence: 99%

“…Thymoquinone (TQ), the most abundant component of black seed oil, has been reported to exhibit antioxidant (4)(5)(6), antiinflammatory, and chemopreventive (7-9) effects. For instance, TQ has been shown to suppress the proliferation of various tumor cells, including colorectal carcinoma, breast adenocarcinoma, osteosarcoma, ovarian carcinoma, myeloblastic leukemia, and pancreatic carcinoma (7,(10)(11)(12)(13)(14), although it is minimally toxic to normal cells (15).…”

Section: Introductionmentioning

confidence: 99%

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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

297

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: Discussionmentioning

confidence: 99%

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

297

218

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“…Cell proliferation (Fig. 1A) and cell viability ( A c c e p t e d M a n u s c r i p t respond to TQ within 24h and at the previously published concentrations [24][25][26][27][28].…”

Section: Tq Inhibits Cell Growth and Induces Cell Cycle Arrest Of Jurmentioning

confidence: 62%

“…It has been suggested that TQ, as a DNA damaging agent, is a potential reactive oxygen species (ROS) producer which exerts its anti-cancer effects by inhibiting cell growth, arresting cell cycle progression and inducing subsequently apoptosis [23][24][25][26][27][28][29]. p53-dependent [26] and p53-independent pathways [23,27] have been evidenced to explain the cellular actions of TQ.…”

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confidence: 99%

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Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1

Alhosin

Abusnina

Achour

et al. 2010

Biochemical Pharmacology

130

116

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The salvage anti-tumoral pathway which implicates the p53-related p73 gene is not yet fully characterized. We therefore attempted to identify the up-and down-stream events involved in the activation of the p73-dependent pro-apoptotic pathway, by focusing on the anti-apoptotic and epigenetic integrator UHRF1 which is essential for cell cycle progression. For this purpose, we analyzed the effects of a known anti-neoplastic drug, thymoquinone (TQ), on the p53-deficient acute lymphoblastic leukemia (ALL) Jurkat cell line. Our results showed that TQ inhibits the proliferation of Jurkat cells and induces G1 cell cycle arrest in a dose-dependent manner. Moreover, TQ treatment triggers programmed cell death, production of reactive oxygen species (ROS) and alteration of the mitochondrial membrane potential (m). TQ-induced apoptosis, confirmed by the presence of hypodiploid G0/G1 cells, is associated with a rapid and sharp re-expression of p73 and dose-dependent changes of the levels of caspase-3 cleaved subunits. These modifications are accompanied by a dramatic down-regulation of UHRF1 and two of its main partners, namely DNMT1 and HDAC1, which are all involved in the epigenetic code regulation. Knockdown of p73 expression restores UHRF1 expression, reactivates cell cycle progression and inhibits TQ-induced apoptosis. Altogether our results showed that TQ mediates its growth inhibitory effects on ALL p53-mutated cells via the activation of a p73-dependent mitochondrial and cell cycle checkpoint signaling pathway which subsequently targets UHRF1.

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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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In vitro inhibition of growth and induction of apoptosis in cancer cell lines by thymoquinone

Cited by 150 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

Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1

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

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