Institute for Biological Research, Department of Neurobiology, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
Food Chem Toxicol. 2011 Dec;49(12):3165-73. doi: 10.1016/j.fct.2011.09.035. Epub 2011 Oct 5.
Jatrophane diterpenes were shown to be inhibitors of P-glycoprotein (P-gp). There are also evidences on their microtubule-interacting activity in cancer cells. We evaluated new anti-cancer characteristics of two jatrophane type compounds from Euphorbia dendroides. For that purpose, the model system of sensitive non-small cell lung cancer cell line (NCI-H460) and its resistant counterpart (NCI-H460/R) was used. Although both jatrophanes showed inhibitory effect on cancer cell growth, they were non-toxic for peripheral blood mononuclear cells (PBMC). We examined their effects in combination with paclitaxel (PTX), a well-known mitotic spindle interacting chemotherapeutic. Jatrophanes overcome PTX resistance in concentration-dependent manner in MDR cancer cell line (NCI-H460/R). We observed that this synergistic effect is not caused merely by P-gp inhibition. In combination with PTX, jatrophanes induce cell killing and change cell cycle distribution leading to G2/M arrest. Furthermore, they exert an anti-angiogenic effect by decreasing the vascular endothelial growth factor (VEGF) secretion. The reduction of the level of mdr1 mRNA expression in sensitive cells, suggests that these compounds could not contribute to the development of resistance. In conclusion, present study provides a rational basis for the new cancer treatment approach with jatrophanes that are non-toxic to normal cells and have new favorable anti-cancer characteristics.
巴豆烷二萜被证明是 P-糖蛋白（P-gp）的抑制剂。它们在癌细胞中的微管相互作用活性也有证据。我们评估了两种来自大戟属植物的巴豆烷型化合物在非小细胞肺癌细胞系（NCI-H460）及其耐药细胞系（NCI-H460/R）中的新抗癌特性。为此，使用了敏感的非小细胞肺癌细胞系（NCI-H460）及其耐药细胞系（NCI-H460/R）作为模型系统。尽管这两种巴豆烷都显示出对癌细胞生长的抑制作用，但它们对外周血单核细胞（PBMC）没有毒性。我们研究了它们与紫杉醇（PTX）联合使用的效果，PTX 是一种已知的有丝分裂纺锤体相互作用的化疗药物。巴豆烷以浓度依赖的方式克服 MDR 癌细胞系（NCI-H460/R）中的 PTX 耐药性。我们观察到这种协同作用不仅仅是由 P-gp 抑制引起的。与 PTX 联合使用时，巴豆烷诱导细胞杀伤并改变细胞周期分布，导致 G2/M 期阻滞。此外，它们通过降低血管内皮生长因子（VEGF）的分泌发挥抗血管生成作用。敏感细胞中 mdr1 mRNA 表达水平的降低表明，这些化合物不会导致耐药性的发展。总之，本研究为巴豆烷的新癌症治疗方法提供了合理的依据，因为它们对正常细胞没有毒性，并具有新的有利的抗癌特性。
