Molecular targeting therapy for anticancer drug-resistant cancer cells derived from uterus and ovary

[1]表观遗传调控和癌细胞抗癌药物敏感性的变化。(1)启动子甲基化与抗癌药物敏感性：我们最近报道了获得性顺铂耐药的新机制，这是一种极强的顺铂耐药细胞RNA翻译障碍，我们用我们实验室建立的顺铂耐药宫颈癌细胞株进行了研究。接下来，我们检测了宫颈癌细胞的去甲基化效应和其他抗癌药物耐药性，子宫内膜癌细胞和卵巢癌细胞的去甲基化效应和顺铂耐药性。结果，去甲基化治疗部分抑制了宫颈癌细胞对拓扑异构酶I抑制剂的耐药性(提交的制剂)。对拓扑异构酶I抑制剂的抗药性与启动子高甲基化呈正相关，如在耐顺铂的宫颈癌细胞变种中发现的那样。基因表达谱研究未发现任何恢复的…更多的因素与高甲基化治疗的药物敏感性调节有关。细胞内信号转导抑制剂和去甲基化处理的实验尚未发现任何药物敏感性恢复分子。(2)DAPK表达与抗癌药物敏感性的关系分析：DAPK的表达很容易受到启动子甲基化的调节，并与CDDP耐药机制有关。因此，我们研究了DAPK表达与去甲基化效应的关系，以及siRNA-DAPK基因敲除与CDDP敏感性的关系。去甲基化处理抑制了耐药，而DAPK表达增加。恢复的药物敏感性被认为是除DAPK以外的未知甲基化调节分子。DAPK基因敲除部分抑制顺铂耐药和VP16耐药，完全抑制5-FU耐药。[2]抗肿瘤药物抗凋亡信号的鉴定为建立耐药肿瘤的分子靶向治疗：在某些抗肿瘤药物成分中，鉴定出几个对抗癌药物有较强抑制活性的分子(准备提交)。在此基础上，进一步对细胞内信号转导机制进行了研究。(1)细胞内信号转导机制的研究。MAPKK和DAPK中的任何一个可能与这些信号有关，目前正在调查中。目前正在对信使核糖核酸图谱分析和siRNA实验进行研究。较少

[1] Epigenetic regulation and changes in anticancer drug-sensitivities of the cancer cells.(1) Promoter hypermethylation and anticancer drug-sensitivities: We have recently reported the novel mechanism in acquired CDDP-resistance, an extremely strong impairment of RNA translation in CDDP-resistant cells, which was investigated with the CDDP-resistant cervical cancer cell lines established originally in our lab. Next, we have examined de-methylation effects and other anticancer drug-resistances in the cervical cancer cells, de-methylation effects and CDDP-resistances in endometrial cancer cells and ovarian cancer cells. As a result, demethylation treatment partially suppressed the resistance to topoisomelase I inhibitor in the cervical cancer cells (preparation in submission). Resistance to topoisomelase I inhibitor showed a positive relation to the promoter hypermethylation, as found in the CDDP-resistant cervical cancer cell variants. mRNA profiling study did not revealed any recovery … More factors related to drug-sensitivity modulation by hypermethylation treatment. Experiments with intracellular signaling inhibitors and demethylation treatments have not identified any drug-sensitivity recovery molecules yet.(2) Analysis of relationships of DAPK expression and anticancer drug-sensitivities: DAPK expression can be easily regulated by promoter-methylation and have some relations to CDDP-resistance mechanisms. Therefore, relationships of DAPK expression and demethylation effects, and of siRNA-DAPK knockdown and CDDP-sensitivity, were examined. Demethylation treatment inhibited drug-resistance while DAPK expression was increased. Recovered drug-sensitivity was thought to be regulated unknown methylation-regulated molecules except for DAPK. DAPK knockdown partially inhibited CDDP-resistance and VP16-resistance, and completely suppressed 5-FU-resistance.[2] Identification of antiapoptotic signals in some Kampo medicine components against anticancer drugs to establish molecular targeting therapy for drug-resistant cancers: In some Kampo medicine components, several molecules with strong suppressive activities against anticancer drugs were identified (preparation for submission). And then, further experiments were done to identify the intracellular signalings in anti-apoptotic phenomena.(1) Identification of intracellular signaling in the cells stimulated with Kampo medicine components. Either MAPKK and DAPK may have some association with the signals, which are now under investigation. Both mRNA profiling analysis and siRNA experiments are now under investigations. Less