Overcome of drug resistance using agents involving transcription factor expression in drug resistant human cancer cells

在这项研究中，通过对转录因子（TF）的表达具有抑制作用的一些药物克服耐药性已经在各种类型的耐药人癌细胞系上进行了评估。在药物敏感细胞系中，肿瘤坏死因子α和干扰素γ诱导NF-κ B的活性，并诱导细胞凋亡。戊氧基茶碱、阿司匹林和乙酰半胱氨酸可抑制NF-κ B的活性，但可诱导细胞凋亡。在耐药细胞系中，正常培养条件下NF-κ B活性升高。它被上述药物抑制，并实现了耐药性的中度克服。在AraC抗性细胞系中，NF-κ B以及Sp-1和Sp-2被激活，表明在AraC抗性中起重要作用。Pentoxyfilline和FK 506抑制这些TF的活性，但耐药性水平略有克服。在耐药细胞系中，观察到热休克蛋白（HSPs）在细胞质和细胞核中的表达增加，表明其在耐药中的作用，但机制尚不清楚。Pentoxyfilline和FK 506可降低HSPs的表达，并略有增强抗癌作用。这些药物是直接作用于热休克蛋白，还是通过TBS作用于热休克蛋白，尚需进一步研究，联合抗癌药物和抑制TF的药物可能是克服耐药的有效方法。

In this study the overcome of drug resistance by some agents having a inhibitory effect on the expression of transcription factors (TFs) has been evaluated on various types of drug resistant human cancer cell lines. In drug-sensitive cell lines, the activity of NF-kappa B was induced by tumor necrosis factor alpha and interferon gamma and apoptosis was induced. Pentoxyfilline, aspirin and acetyl cysteine can inhibit the activity of NF-kappa B but apoptosis was induced. In drug resistant cell lines, the activity of NF-kB was elevated under normal culture condition. It was inhibited by the agents described above and moderate overcome of drug resistance was achieved. In AraC resistant cell lines, NF-kB as well as Sp-1 and Sp-2 were activated, suggesting an important role in AraC resistance. Pentoxyfilline and FK506 inhibited the activity of these TFs but levels of drug resistance was slightly overcame. In drug resistant cell lines, elevated expression of heat shock proteins (HSPs) was observed in both cytoplasm and nucleus, suggesting a role in drug resistance with unknown mechanism. Pentoxyfilline and FK506 decreased the expression of HSPs and enhanced anticancer effect slightly. Further study is needed to elucidate whether these agents affect HSPs directly or through TBS.The combination with anticancer drugs and agents inhibiting TFs may be effective for overcome drug resistance.