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

在这项研究中，评价了一些对转录因子(TF)的表达具有抑制作用的药物在不同类型的人类耐药癌细胞系上克服耐药性的作用。在药物敏感细胞系中，肿瘤坏死因子-α和干扰素-γ可诱导核因子-kappaB的活性，并诱导细胞凋亡。戊四氮、阿司匹林和乙酰半胱氨酸可抑制核因子-kappaB的活性，但可诱导细胞凋亡。在耐药细胞系中，在正常培养条件下，核因子-kB活性升高。上述药物对其有抑制作用，并可适度克服耐药。在AraC耐药细胞系中，NF-kB、Sp-1和Sp-2均被激活，提示其在AraC耐药中起重要作用。戊四氢叶酸和FK506可抑制这些因子的活性，但抗药性水平略有改善。在耐药细胞系中，热休克蛋白(HSPs)在胞浆和胞核均有高表达，提示热休克蛋白在耐药中的作用机制不明。戊四氢叶酸和FK506可降低HSPs的表达，增强抗癌作用。这些药物是直接作用于热休克蛋白，还是通过热休克蛋白作用于热休克蛋白，尚需进一步研究。与抗癌药物和抑制热休克蛋白的药物联合使用可能有效地克服耐药性。

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.