Abstract
BackgroundThymoquinone (TQ) is a compound extracted from Black Caraway seeds of Nigella Sativa and is active against various cancers. Cisplatin (CDDP) is the most active chemotherapeutic agent in Lung Cancer. Here we report activity of TQ against non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines alone and in combination with Cisplatin (CDDP).MethodsFor proliferation MTT assay, cell viability trypan blue assay and for apoptosis Annexin-V FITC assay were used in NCI-H460 and NCI-H146 cell lines. Inhibition of invasion by TQ was assessed using Matrigel assay and its affect on release of various cytokines was determined using RayBio Human Cytokine detection kit. Mouse xenograft model using NCI-H460 was used to determine in vivo activity of TQ and CDDP. Inhibition of LPS induced NF-κB expression by TQ was determined using transgenic mice expressing a luciferase reporter.ResultsTQ was able to inhibit cell proliferation, reduce cell viability and induce apoptosis. TQ at 100 μM and CDDP at 5 μM inhibited cell proliferation by nearly 90% and the combination showed synergism. TQ was able to induced apoptosis in both NCI-H460 and NCI-H146 cell lines. TQ also appears to affect the extracellular environment inhibiting invasion and reducing the production of two cytokines ENA-78 and Gro-alpha which are involved in neo-angiogenesis. Using a mouse xenograft model we were able to demonstrate that combination of TQ and CDDP was well tolerated and significantly reduced tumor volume and tumor weight without additional toxicity to the mice. In the combination arms (TQ5 mg/kg/Cis 2.5 mg/kg) tumor volume was reduced by 59% and (TQ20 mg/kg/Cis 2.5 mg/kg) by 79% as compared to control which is consistent with in vitro data. TQ down regulated NF-κB expression which may explain its various cellular activities and this activity may prove useful in overcoming CDDP resistance from over expression of NF-κB.ConclusionsThus TQ and CDDP appear to be an active therapeutic combination in lung cancer.
Highlights
Thymoquinone (TQ) is a compound extracted from Black Caraway seeds of Nigella Sativa and is active against various cancers
Cells were grown in RPMI 1640 (Cell gro) supplemented with 10% Fetal bovine serum (FBS), 1% Penicillin and Streptomycin in a humidified incubator with 5% CO2 at 37°C. 1) Cell proliferation assay NCI-H460 cells (NSCLC cell line) were seeded at a density of 5,000 cells per well in 96 well plates and after 24 hrs cells were treated with 80 μM and 100 μM Thymoquinone (TQ) (Sigma Aldrich, St Louis MO) in 0.1% DMSO, 1.25 μM, 2.5 μM and 5.0 μM Cisplatin (CDDP) (Sigma Aldrich, St Louis MO) or TQ and CDDP at various combinations as noted
2) TQ enhances the effect of Cisplatin with synergism between the two agents When the NCI-H460 cells were grown in the presence or absence of TQ and CDDP it was apparent that the combined effect of TQ and CDDP was more than the each agent alone
Summary
Thymoquinone (TQ) is a compound extracted from Black Caraway seeds of Nigella Sativa and is active against various cancers. Cisplatin (CDDP) is the most active chemotherapeutic agent in Lung Cancer. We report activity of TQ against non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines alone and in combination with Cisplatin (CDDP). In the US alone it is estimated that in the year 2008, approximately 215,020 new cases of lung cancer were diagnosed and an estimated 161,480 deaths were reported. The most active chemotherapeutic agent for the treatment of NSCLC and SCLC is cisplatin (CDDP) which is used in a doublet with other agents such as paclitaxel, gemcitabine and docetaxel [5]. The response rate in NSCLC from CDDP alone is about 20% and in combination with a second agent improves to about 26% [6]
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