Worthen D R, Ghosheh O A, Crooks P A
Natural Products Chemistry Laboratory, Tobacco and Health Research Institute, Lexington, KY 40536, USA.
Anticancer Res. 1998 May-Jun;18(3A):1527-32.
A crude gum, a fixed oil and two purified components of Nigella sativa seed, thymoquinone (TQ) and dithymoquinone (DIM), were assayed in vitro for their cytotoxicity for several parental and multi-drug resistant (MDR) human tumor cell lines. Although as much as 1% w/v of the gum or oil was devoid of cytotoxicity, both TQ and DIM were cytotoxic for all of the tested cell lines (IC50's 78 to 393 microM). Both the parental cell lines and their corresponding MDR variants, over 10-fold more resistant to the standard antineoplastic agents doxorubicin (DOX) and etoposide (ETP), as compared to their respective parental controls, were equally sensitive to TQ and DIM. The inclusion of the competitive MDR modulator quinine in the assay reversed MDR Dx-5 cell resistance to DOX and ETP by 6- to 16-fold, but had no effect on the cytotoxicity of TQ or DIM. Quinine also increased MDR Dx-5 cell accumulation of the P-glycoprotein substrate 3H-taxol in a dose-dependent manner. However, neither TQ nor DIM significantly altered cellular accumulation of 3H-taxol. The inclusion of 0.5% v/v of the radical scavenger DMSO in the assay reduced the cytotoxicity of DOX by as much as 39%, but did not affect that of TQ or DIM. These studies suggest that TQ and DIM, which are cytotoxic for several types of human tumor cells, may not be MDR substrates, and that radical generation may not be critical to their cytotoxic activity.
对黑种草籽的一种粗胶、一种固定油以及两种纯化成分百里醌（TQ）和双百里醌（DIM）进行了体外测定，检测它们对几种亲本和多药耐药（MDR）人类肿瘤细胞系的细胞毒性。尽管高达1% w/v的粗胶或油没有细胞毒性，但TQ和DIM对所有测试细胞系均具有细胞毒性（IC50为78至393 microM）。与各自的亲本对照相比，亲本细胞系及其相应的MDR变体对标准抗肿瘤药物阿霉素（DOX）和依托泊苷（ETP）的耐药性高出10倍以上，但它们对TQ和DIM同样敏感。在测定中加入竞争性MDR调节剂奎宁可使MDR Dx - 5细胞对DOX和ETP的耐药性逆转6至16倍，但对TQ或DIM的细胞毒性没有影响。奎宁还以剂量依赖性方式增加了MDR Dx - 5细胞对P - 糖蛋白底物3H - 紫杉醇的摄取。然而，TQ和DIM均未显著改变3H - 紫杉醇的细胞摄取量。在测定中加入0.5% v/v的自由基清除剂二甲基亚砜（DMSO）可使DOX的细胞毒性降低多达39%，但不影响TQ或DIM的细胞毒性。这些研究表明，对几种类型的人类肿瘤细胞具有细胞毒性的TQ和DIM可能不是MDR底物，并且自由基的产生对其细胞毒性活性可能并不关键。
