Feist-Weiller Cancer Center, Louisiana State University, Shreveport, LA 71130 USA.
J Exp Clin Cancer Res. 2010 Jul 1;29(1):87. doi: 10.1186/1756-9966-29-87.
BACKGROUND: 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. 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). METHODS: For 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-kappaB expression by TQ was determined using transgenic mice expressing a luciferase reporter. RESULTS: TQ was able to inhibit cell proliferation, reduce cell viability and induce apoptosis. TQ at 100 microM and CDDP at 5 muM 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-kappaB expression which may explain its various cellular activities and this activity may prove useful in overcoming CDDP resistance from over expression of NF-kappaB. CONCLUSIONS: Thus TQ and CDDP appear to be an active therapeutic combination in lung cancer.
背景：百里醌（TQ）是从黑种草种子中提取的一种化合物，对各种癌症具有活性。顺铂（CDDP）是肺癌中最有效的化疗药物。在这里，我们报告了 TQ 单独和联合顺铂（CDDP）对非小细胞肺癌（NSCLC）和小细胞肺癌（SCLC）细胞系的活性。 方法：对于增殖 MTT 测定，使用细胞活力台盼蓝测定法和凋亡 Annexin-V FITC 测定法在 NCI-H460 和 NCI-H146 细胞系中进行。使用 Matrigel 测定法评估 TQ 对侵袭的抑制作用，并使用 RayBio 人类细胞因子检测试剂盒测定其对各种细胞因子释放的影响。使用 NCI-H460 的小鼠异种移植模型来确定 TQ 和 CDDP 的体内活性。使用表达荧光素酶报告基因的转基因小鼠来确定 TQ 对 LPS 诱导的 NF-kappaB 表达的抑制作用。 结果：TQ 能够抑制细胞增殖，降低细胞活力并诱导细胞凋亡。TQ 为 100 μM，CDDP 为 5 μM，几乎抑制了 90%的细胞增殖，联合用药表现出协同作用。TQ 能够诱导 NCI-H460 和 NCI-H146 细胞系中的细胞凋亡。TQ 似乎还会影响细胞外环境，抑制侵袭并减少两种细胞因子 ENA-78 和 Gro-alpha 的产生，这两种细胞因子参与新生血管形成。使用小鼠异种移植模型，我们能够证明 TQ 和 CDDP 的联合使用耐受良好，并且没有对小鼠产生额外的毒性，而显著降低了肿瘤体积和肿瘤重量。在联合治疗组（TQ5mg/kg/Cis2.5mg/kg）中，肿瘤体积减少了 59%，（TQ20mg/kg/Cis2.5mg/kg）减少了 79%，与体外数据一致。TQ 下调 NF-kappaB 表达，这可能解释了其各种细胞活性，并且这种活性可能有助于克服 NF-kappaB 过度表达导致的 CDDP 耐药性。 结论：因此，TQ 和 CDDP 似乎是肺癌的一种有效治疗联合用药。
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