Nigella Abstracts 4

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Thymoquinone in the clinical treatment of cancer: Fact or fiction
            (Abukhader, 2013) Download
Thymoquinone (TQ) is the bioactive phytochemical constituent of the seeds oil of Nigella sativa. In vitro and in vivo research has thoroughly investigated the anticancer effects of TQ against several cancer cell lines and animal models. As a result, a considerable amount of information has been generated from research thus providing a better understanding of the anti-proliferating activity of this compound. Therefore, it is appropriate that TQ should move from testing on the bench to clinical experiments. The purpose of this review is to highlight the potential of TQ as an anticancer agent and the chances of this compound in the clinical treatment of cancer, with special attention on breast cancer treatment.

Cytotoxicity of Nigella sativa seed oil and extract against human lung cancer cell line.
            (Al-Sheddi et al., 2014) Download
Nigella sativa (N sativa), commonly known as black seed, has been used in traditional medicine to treat many diseases. The antioxidant, anti-inflammatory, and antibacterial activities of N sativa extracts are well known. Therefore, the present study was designed to investigate the anticancer activity of seed extract (NSE) and seed oil (NSO) of N sativa against a human lung cancer cell line. Cells were exposed to 0.01 to 1 mg/ml of NSE and NSO for 24 h, then percent cell viability was assessed by 3-(4, 5-dimethylthiazol-2yl)-2, 5-biphenyl tetrazolium bromide (MTT) and neutral red uptake (NRU) assays, and cellular morphology by phase contrast inverted microscopy. The results showed NSE and NSO significantly reduce the cell viability and alter the cellular morphology of A-549 cells in a concentration dependent manner. The percent cell viability was recorded as 75%, 50%, and 26% at 0.25, 0.5, and 1 mg/ml of NSE by MTT assay and 73%, 48%, and 23% at 0.25, 0.5, and 1 mg/ml of NSE by NRU assay. Exposure to NSO concentrations of 0.1 mg/ml and above for 24 h was also found to be cytotoxic. The decrease in cell viability at 0.1, 0.25, 0.5, and 1 mg/ml of NSO was recorded to be 89%, 52%, 41%, and 13% by MTT assay and 85%, 52%, 38%, and 11% by NRU assay, respectively. A-549 cells exposed to 0.25, 0.5 and 1 mg/ml of NSE and NSO lost their typical morphology and appeared smaller in size. The data revealed that the treatment of seed extract (NSE) and seed oil (NSO) of Nigella sativa significantly reduce viability of human lung cancer cells.


Finding Novel Antibiotic Substances from Medicinal Plants - Antimicrobial Properties of Nigella Sativa Directed against Multidrug-resistant Bacteria.
            (Bakal et al., 2017) Download
The progressive rise in multidrug-resistant (MDR) bacterial strains poses serious problems in the treatment of infectious diseases. While the number of newly developed antimicrobial compounds has greatly fallen, the resistance of pathogens against commonly prescribed drugs is further increasing. This rise in resistance illustrates the need for developing novel therapeutic and preventive antimicrobial options. The medicinal herb Nigella sativa and its derivatives constitute promising candidates. In a comprehensive literature survey (using the PubMed data base), we searched for publications on the antimicrobial effects of N. sativa particularly directed against MDR bacterial strains. In vitro studies published between 2000 and 2015 revealed that N. sativa exerted potent antibacterial effects against both Gram-positive and Gram-negative species including resistant strains. For instance, N. sativa inhibited the growth of bacteria causing significant gastrointestinal morbidity such as Salmonella, Helicobacter pylori, and Escherichia coli. However, Listeria monocytogenes and Pseudomonas aeruginosa displayed resistance against black cumin seed extracts. In conclusion, our literature survey revealed potent antimicrobial properties of N. sativa against MDR strains in vitro that should be further investigated in order to develop novel therapeutic perspectives for combating infectious diseases particularly caused by MDR strains.

Thymoquinone inhibits matrix metalloproteinase expression in rabbit chondrocytes and cartilage in experimental osteoarthritis.
            (Chen et al., 2010) Download
Thymoquinone (TQ) is the main constituent of Nigella sativa oil, which has been traditionally used against arthritis in the Middle East. In this study, we investigated the effect of TQ against matrix metalloproteinase (MMP) expression in both rabbit chondrocytes and animal mode of osteoarthritis (OA) induced by anterior cruciate ligament transection and tested whether or not nuclear factor kappa B (NF-κB) was involved in this process. TQ down-regulated MMP-1, MMP-3 and MMP-13 expression and up-regulated tissue inhibitors of metalloproteinase-1 expression as assessed by quantitative realtime polymerase chain reaction. In addition, NF-κB p65 protein level as well as its translocation induced by interleukin-1β were inhibited by TQ. Our findings suggest the potential of TQ in the treatment of OA.


 

Nigella sativa oil, nigellone and derived thymoquinone inhibit synthesis of 5-lipoxygenase products in polymorphonuclear leukocytes from rats.
            (El-Dakhakhny et al., 2002) Download
In the present study, Nigella sativa oil (NSO), nigellone (polythymoquinone) and derived thymoquinone were studied to evaluate their effect on the formation of 5-lipoxygenase (5-LO) products from polymorphonuclear leukocytes (PMNL).NSO produced a concentration dependent inhibition of 5-LO products and 5-hydroxy-eicosa-tetra-enoic acid (5-HETE) production with half maximal effects (IC(50)) at 25+/-1 micro g/ml, respectively 24+/-1 micro g/ml. Nigellone caused a concentration-related inhibition of 5-HETE production (IC(50): 11.9+/-0.3 micro g/ml). Moreover thymoquinone, the active principle of NSO inhibited the production of 5-LO products (IC(50): 0.26+/-0.02 micro g/ml) and 5-HETE production (IC(50): 0.36+/-0.02 micro g/ml) in a similar way. The effects are probably due to an antioxidative action. The data may in part explain the effect of the oil, its derived thymoquinone and nigellone in ameliorating inflammatory diseases.

Thymoquinone-induced Neu4 sialidase activates NFκB in macrophage cells and pro-inflammatory cytokines in vivo.
            (Finlay et al., 2010) Download
Thymoquinone (TQ) derived from the nutraceutical black cumin oil has been reported to be a novel agonist of Neu4 sialidase activity in live cells (Glycoconj J DOI 10.1007/s10719-010-9281-6). The activation of Neu4 sialidase on the cell surface by TQ was found to involve GPCR-signaling via membrane targeting of Gαi subunit proteins and matrix metalloproteinase-9 activation. Contrary to other reports, TQ had no anti-inflammatory effects in vitro. Here, we show that MyD88/TLR4 complex formation and subsequent NFκB activation are induced by the Neu4 activity associated with TQ-stimulated live primary bone marrow (BM) macrophage cells from WT and Neu1-deficient mice, HEK-TLR4/MD2 cells and BMC-2 macrophage cell line but not with primary macrophage cells from Neu4-knockout mice. Tamiflu (oseltamivir phosphate), pertussis toxin (PTX), a specific inhibitor of Gαi proteins of G-protein coupled receptor (GPCR) and the broad range inhibitor of matrix metalloproteinase (MMP) galardin applied to live primary BM macrophage cells completely block TQ-induced MyD88/TLR4 complex formation. Using immunocytochemistry and western blot analyses, Tamiflu, galardin and PTX inhibit NFκB activation induced by Neu4 activity associated with TQ-stimulated BMC-2 cells, HEK-TLR4/MD2 cells and primary BM macrophages from WT mice. EMSA analyses on HEK-TLR4/MD2 nuclear cell extracts confirm the nuclear localization and DNA binding of TQ-induced NFκB activation in a biphasic manner within 30 min. Co-immunoprecipitation experiments reveal for the first time that MMP-9 may be an important intermediate link in the TQ-induced Neu4 activity circuitously targeting TLR4 receptors. Central to this process is that Neu4 forms a complex with MMP-9, which is already bound to TLR4 receptors. Fluorescence spectrophotometer analyses of live CD14-THP1 cells treated with TQ show Neu4 sialidase activity over 5 min. Using flow cytometry analyses, CD14-THP1 cells treated with TQ express stable protein levels of Neu4, TLR4 and MMP9 on the cell surface over 30 min except for a marked diminution of MMP9 at 15 min. Using cytokine array profiling analyses of serum, Neu4-knockout mice respond poorly to TQ in producing pro-inflammatory cytokines and chemokines after 5-h treatment compared to the wild-type or hypomorphic cathepsin A mice with a secondary 90% Neu1 deficient mice. Our findings establish an unprecedented signaling paradigm for TQ-induced Neu4 sialidase activity. It signifies that MMP-9 forms an important molecular signaling platform in complex with TLR4 receptors at the ectodomain and acts as the intermediate link for TQ-induced Neu4 sialidase in generating a functional receptor with subsequent NFκB activation and pro-inflammatory cytokine production in vivo.

Antineoplastic effects of bee honey and Nigella sativa on hepatocellular carcinoma cells.
            (Hassan et al., 2012) Download
OBJECTIVES:  To evaluate in vitro antitumor effects of bee honey (BH) and Nigella sativa (NS) on HepG2 through their antioxidant and apoptotic activities. METHODS:  HepG2 cell line was treated with different concentrations of diluted unfractionated BH and different concentrations of alcohol extract of NS. Exposure lasted for different time durations (6-72 hours), both dose-response and time course-response were conducted. Cell viability was tested by trypan blue exclusion test. Total antioxidant status and caspase-3 activity were estimated in the cell lysate. Nitric oxide levels were measured in culture supernatants of both treated and untreated HepG2 at all indicated times. RESULTS:  Treatment of HepG2 cells with BH and NS leads to a significant decrease in both the number of viable HepG2 cells and the levels of nitric oxide on one hand, but improvement of the total antioxidant status and caspase-3 activity on the other, especially in HepG2 cells treated with higher doses of BH and NS (20% and 5000 μg/mL, respectively) and for longer duration (72 hours). CONCLUSIONS:  BH and NS are effective in reducing the viability of HepG2 cells, improving their antioxidant status and inducing their apoptotic death.

Cellular responses with thymoquinone treatment in human breast cancer cell line MCF-7.
            (Motaghed et al., 2013) Download
BACKGROUND:  Nigella sativa or black seed extract has been reported to show various medicinal benefits. Thymoquinone which is an active compound of its seed has been reported to contain anti-cancer properties. OBJECTIVE:  The study addressed the anti-cancer efficiency of long-term in vitro treatment with thymoquinone towards human breast cancer cell lines MCF-7. MATERIALS AND METHODS:  Cell proliferation was determined with CellTiter 96 Aqueous. Non-Radioactive Cell Proliferation Assay Kit. It was followed with trypan blue exclusion test to determine the percentage of viable cells. The study incorporated cell cycle assay to distinguish cell distribution at various cell cycle phases using Cycletest Plus DNA Reagent Kit. The apoptosis detection kit was used to determine the percentage of apoptotic and necrotic cells using flow cytometry. RESULTS:  The 50% inhibitory concentration (IC50) value determined using the proliferation assay was 25 μM thymoquinone. Late apoptotic cell percentage increased rapidly when treatment duration was increased to 24 h with 25 and 100 μM thymoquinone. Further analysis using cell cycle assay showed thymoquinone inhibition of breast cancer cell proliferation at minimal dose 25 μM and led to S phase arrest significantly at 72 h treatment (P = 0.009). It was also noted elevation sub-G1 peak following treatment with 25 μM thymoquinone for 12 h. Increase in thymoquinone to 50 μM caused G2 phase arrest at each time-point studied. CONCLUSION:  In general thymoquinone showed sustained inhibition of breast cancer cell proliferation with long-term treatment. Specificity of phase arrest was determined by thymoquinone dose.

Effect of Nigella sativa supplementation on obesity indices: A systematic review and meta-analysis of randomized controlled trials.
            (Mousavi et al., 2018) Download
BACKGROUND & OBJECTIVE(S):  No meta-analysis is available on the effect of Nigella sativa (NS) on obesity indices. This systematic review and meta-analysis was conducted to systematically review the available Randomized Clinical Trials (RCTs) that examined the effects of NS on Body Weight (BW), Body Mass index (BMI), and Waist Circumference (WC) in adults. METHODS:  Relevant articles published up to January 2018 were searched through PubMed/Medline, SCOPUS, Cochrane Library, and Google Scholar databases, using relevant keywords. All RCTs that examined the effect of NS supplementation on BW, BMI, or WC were included. RESULTS:  Overall, thirteen RCTs, including 875 subjects (64% males) were included in this study. Combining effect sizes from ten studies, NS supplementation significantly reduced BW (Weighted Mean Differences (WMD): -1.76 kg, 95% CI: -3.34 to -0.17, I CONCLUSIONS:  We find a significant effect of NS supplementation on BW and BMI in adults. However, the effect of NS supplementation on WC was not significant in this meta-analysis.

From here to eternity - the secret of Pharaohs: Therapeutic potential of black cumin seeds and beyond.
            (Padhye et al., 2008) Download
Over many centuries humans have been mining the bounties of nature for discovering substances that have been used for the treatment of all human diseases; many such remedies are useful even today as modern day medicine. Emerging evidence also suggests that the search is still continuing for harnessing active compounds from nature in combating human illnesses although pharmaceutical industries are equally active for synthesizing small molecule compounds as novel therapeutics. The lesson learned over many centuries clearly suggests that further sophisticated search for finding compounds from natural resources together with robust characterization and chemical synthesis will lead to the discovery of novel drugs that may have high therapeutic efficacy against all human diseases including cancer. Black cumin seed (Nigella sativa) oil extracts have been used for many centuries for the treatment of many human illnesses, and more recently the active compound found in black seed oil, viz. thymoquinone (TQ) has been tested for its efficacy against several diseases including cancer. However, further research is needed in order to assess the full potential of TQ as a chemopreventive and/or therapeutic agent against cancers. Here, we have summarized what is known regarding the value of black seed oil and its active compound TQ, and how this knowledge will help us to advance further research in this field by creating awareness among scientists and health professionals in order to appreciate the medicinal value of TQ and beyond.

Thymoquinone induces mitochondria-mediated apoptosis in acute lymphoblastic leukaemia in vitro.
            (Salim et al., 2013) Download
There has been a growing interest in naturally occurring compounds from traditional medicine with anti-cancer potential. Nigella sativa (black seed) is one of the most widely studied plants. This annual herb grows in countries bordering the Mediterranean Sea and India. Thymoquinone (TQ) is an active ingredient isolated from Nigella sativa. The anti-cancer effect of TQ, via the induction of apoptosis resulting from mitochondrial dysfunction, was assessed in an acute lymphocyte leukemic cell line (CEMss) with an IC50 of 1.5 µg/mL. A significant increase in chromatin condensation in the cell nucleus was observed using fluorescence analysis. The apoptosis was then confirmed by Annexin V and an increased number of cellular DNA breaks in treated cells were observed as a DNA ladder. Treatment of CEMss cells with TQ encouraged apoptosis with cell death-transducing signals by a down-regulation of Bcl-2 and up-regulation of Bax. Moreover, the significant generation of cellular ROS, HSP70 and activation of caspases 3 and 8 were also observed in the treated cells. The mitochondrial apoptosis was clearly associated with the S phase cell cycle arrest. In conclusion, the results from the current study indicated that TQ could be a promising agent for the treatment of leukemia.


 

Thymoquinone: fifty years of success in the battle against cancer models.
            (Schneider-Stock et al., 2014) Download
Thymoquinone (TQ), the main active constituent of black seed essential oil, exhibits promising effects against inflammatory diseases and cancer. TQ, modulates signaling pathways that are key to cancer progression, and enhances the anticancer potential of clinical drugs while reducing their toxic side effects. Considering that TQ was isolated 50 years ago, this review focuses on TQ's chemical and pharmacological properties and the latest advances in TQ analog design and nanoformulation. We discuss our current state of knowledge of TQ's adjuvant potential and in vivo antitumor activity and highlight its ability to modulate the hallmarks of cancer.

Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis.
            (Sethi et al., 2008) Download
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-kappaB (NF-kappa B) signaling, we investigated in detail the effect of this quinone on NF-kappa B pathway. As examined by DNA binding, we found that TQ suppressed tumor necrosis factor-induced NF-kappa B activation in a dose- and time-dependent manner and inhibited NF-kappaB activation induced by various carcinogens and inflammatory stimuli. The suppression of NF-kappaB activation correlated with sequential inhibition of the activation of I kappa B alpha kinase, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-kappa B-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-kappa B-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-kappa B activation pathway, as shown here, and thus may have potential in treatment of myeloid leukemia and other cancers.


 

Thymoquinone Inhibits Bone Metastasis of Breast Cancer Cells Through Abrogation of the CXCR4 Signaling Axis.
            (Shanmugam et al., 2018) Download
Overexpression of chemokine receptor type 4 (CXCR4) has been found to be associated with increased cell proliferation, metastasis and also act as an indicator of poor prognosis in patients with breast cancer. Therefore, new agents that can abrogate CXCR4 expression have potential against breast cancer metastasis. In this study, we examined the potential effect of thymoquinone (TQ), derived from the seeds of Nigella sativa, on the expression and regulation of CXCR4 in breast cancer cells. TQ was found to inhibit the expression of CXCR4 in MDA-MB-231 triple negative breast cancer (TNBC) cells in a dose- and time-dependent manner. It was noted that suppression of CXCR4 by TQ was possibly transcriptionally regulated, as treatment with this drug caused down-regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and suppression of NF-κB binding to the CXCR4 promoter. Pretreatment with a proteasome inhibitor and/or lysosomal stabilization did not affect TQ induced suppression of CXCR4. Down-regulation of CXCR4 was further correlated with the inhibition of CXCL12-mediated migration and invasion of MDA-MB-231 cells. Interestingly, it was observed that the deletion of p65 could reverse the observed anti-invasive/anti-migratory effects of TQ in breast cancer cells. TQ also dose-dependently inhibited MDA-MB-231 tumor growth and tumor vascularity in a chick chorioallantoic membrane assay model. We also observed TQ (2 and 4 mg/kg) treatment significantly suppressed multiple lung, brain, and bone metastases in a dose-dependent manner in a metastasis breast cancer mouse model. Interestingly, H&E and immunohistochemical analysis of bone isolated from TQ treated mice indicated a reduction in number of osteolytic lesions and the expression of metastatic biomarkers. In conclusion, the results indicate that TQ primarily exerts its anti-metastatic effects by down-regulation of NF-κB regulated CXCR4 expression and thus has potential for the treatment of breast cancer.

Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis.
            (Vaillancourt et al., 2011) Download
Thymoquinone (TQ) is the major active compound derived from the medicinal Nigella sativa. A few studies have shown that TQ exhibits anti-inflammatory activities in experimental models of rheumatoid arthritis (RA) through mechanisms that are not fully understood. The aim of this work was to evaluate the in vitro and in vivo effects of TQ and to investigate its influence on the major signalling pathways involved in pathophysiological RA changes. We used isolated human RA fibroblast-like synoviocytes (FLS) and a rat adjuvant-induced arthritis model of RA. In isolated RA FLS, TQ (0-10 µM) was not cytotoxic and inhibited slightly lipopolysaccharide (LPS)-induced FLS proliferation and strongly H(2)O(2)-induced 4-hydroxynonenal (HNE) generation. By studying different inflammatory and catabolic factors, we determined that TQ significantly abolished LPS-induced interleukin-1beta (IL-1β), tumour necrosis factor-alpha (TNFα), metalloproteinase-13, cyclooxygenase-2, and prostaglandin E(2). Furthermore, LPS-induced the phosphorylation of p38 mitogen-activated protein kinase, extracellular-regulated kinases ½, and nuclear factor-kappaB-p65 were also blocked by TQ in time-dependent manner. In our experimental RA model, the oral administration of TQ 5 mg/kg/day significantly reduced the serum levels of HNE, IL-1β and TNFα as well as bone turnover markers, such as alkaline phosphatase and tartrate-resistant acid phosphatase. The protective effects of TQ against RA were also evident from the decrease in arthritis scoring and bone resorption. In conclusion, the fact that TQ abolishes a number of factors known to be involved in RA pathogenesis renders it a clinically valuable agent in the prevention of articular diseases, including RA.

Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: the role of p38 MAPK and ROS.
            (Woo et al., 2013) Download
Due to narrow therapeutic window of cancer therapeutic agents and the development of resistance against these agents, there is a need to discover novel agents to treat breast cancer. The antitumor activities of thymoquinone (TQ), a compound isolated from Nigella sativa oil, were investigated in breast carcinoma in vitro and in vivo. Cell responses after TQ treatment were assessed by using different assays including MTT assay, annexin V-propidium iodide staining, Mitosox staining and Western blot. The antitumor effect was studied by breast tumor xenograft mouse model, and the tumor tissues were examined by histology and immunohistochemistry. The level of anti-oxidant enzymes/molecules in mouse liver tissues was measured by commercial kits. Here, we show that TQ induced p38 phosphorylation and ROS production in breast cancer cells. These inductions were found to be responsible for TQ's anti-proliferative and pro-apoptotic effects. Moreover, TQ-induced ROS production regulated p38 phosphorylation but not vice versa. TQ treatment was found to suppress the tumor growth and this effect was further enhanced by combination with doxorubicin. TQ also inhibited the protein expression of anti-apoptotic genes, such as XIAP, survivin, Bcl-xL and Bcl-2, in breast cancer cells and breast tumor xenograft. Reduced Ki67 and increased TUNEL staining were observed in TQ-treated tumors. TQ was also found to increase the level of catalase, superoxide dismutase and glutathione in mouse liver tissues. Overall, our results demonstrated that the anti-proliferative and pro-apoptotic effects of TQ in breast cancer are mediated through p38 phosphorylation via ROS generation.

 


References

Abukhader, MM (2013), ‘Thymoquinone in the clinical treatment of cancer: Fact or fiction’, Pharmacogn Rev, 7 (14), 117-20. PubMed: 24347919
Al-Sheddi, ES, et al. (2014), ‘Cytotoxicity of Nigella sativa seed oil and extract against human lung cancer cell line.’, Asian Pac J Cancer Prev, 15 (2), 983-87. PubMed: 24568529
Bakal, SN, S Bereswill, and MM Heimesaat (2017), ‘Finding Novel Antibiotic Substances from Medicinal Plants - Antimicrobial Properties of Nigella Sativa Directed against Multidrug-resistant Bacteria.’, Eur J Microbiol Immunol (Bp), 7 (1), 92-98. PubMed: 28386474
Chen, WP, et al. (2010), ‘Thymoquinone inhibits matrix metalloproteinase expression in rabbit chondrocytes and cartilage in experimental osteoarthritis.’, Exp Biol Med (Maywood), 235 (12), 1425-31. PubMed: 21127340
El-Dakhakhny, M, et al. (2002), ‘Nigella sativa oil, nigellone and derived thymoquinone inhibit synthesis of 5-lipoxygenase products in polymorphonuclear leukocytes from rats.’, J Ethnopharmacol, 81 (2), 161-64. PubMed: 12065147
Finlay, TM, et al. (2010), ‘Thymoquinone-induced Neu4 sialidase activates NFκB in macrophage cells and pro-inflammatory cytokines in vivo.’, Glycoconj J, 27 (6), 583-600. PubMed: 20697956
Hassan, MI, et al. (2012), ‘Antineoplastic effects of bee honey and Nigella sativa on hepatocellular carcinoma cells.’, Integr Cancer Ther, 11 (4), 354-63. PubMed: 21147814
Motaghed, M, FM Al-Hassan, and SS Hamid (2013), ‘Cellular responses with thymoquinone treatment in human breast cancer cell line MCF-7.’, Pharmacognosy Res, 5 (3), 200-6. PubMed: 23900121
Mousavi, SM, et al. (2018), ‘Effect of Nigella sativa supplementation on obesity indices: A systematic review and meta-analysis of randomized controlled trials.’, Complement Ther Med, 38 48-57. PubMed: 29857879
Padhye, S, et al. (2008), ‘From here to eternity - the secret of Pharaohs: Therapeutic potential of black cumin seeds and beyond.’, Cancer Ther, 6 (b), 495-510. PubMed: 19018291
Salim, LZ, et al. (2013), ‘Thymoquinone induces mitochondria-mediated apoptosis in acute lymphoblastic leukaemia in vitro.’, Molecules, 18 (9), 11219-40. PubMed: 24036512
Schneider-Stock, R, et al. (2014), ‘Thymoquinone: fifty years of success in the battle against cancer models.’, Drug Discov Today, 19 (1), 18-30. PubMed: 24001594
Sethi, G, KS Ahn, and BB Aggarwal (2008), ‘Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis.’, Mol Cancer Res, 6 1059-70. PubMed: 18567808
Shanmugam, MK, et al. (2018), ‘Thymoquinone Inhibits Bone Metastasis of Breast Cancer Cells Through Abrogation of the CXCR4 Signaling Axis.’, Front Pharmacol, 9 1294. PubMed: 30564115
Vaillancourt, F, et al. (2011), ‘Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis.’, J Cell Biochem, 112 (1), 107-17. PubMed: 20872780
Woo, CC, et al. (2013), ‘Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: the role of p38 MAPK and ROS.’, PLoS One, 8 (10), e75356. PubMed: 24098377