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

肿瘤细胞抗肿瘤药物敏感性的表观遗传调控和变化。(1)启动子超甲基化和抗癌药物敏感性：我们最近报道了获得性cddp耐药的新机制，这是一种cddp耐药细胞中RNA翻译的极强损伤，我们用我们实验室最初建立的cddp耐药宫颈癌细胞系进行了研究。接下来，我们研究了宫颈癌细胞的去甲基化作用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作用和cddp耐药性。结果，去甲基化处理部分抑制了宫颈癌细胞对拓扑异构酶I抑制剂的耐药性（已提交的制剂）。对拓扑异构酶I抑制剂的抗性与启动子超甲基化呈正相关，这在cddp抗性宫颈癌细胞变体中发现。mRNA谱分析研究未发现任何恢复…更多因素与高甲基化治疗药物敏感性调节有关。细胞内信号抑制剂和去甲基化治疗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的表达容易受到启动子甲基化的调控，与cddp耐药机制有一定关系。因此，我们检测了DAPK表达与去甲基化效应的关系，以及siRNA-DAPK敲低与cddp敏感性的关系。去甲基化处理抑制了耐药，同时增加了DAPK的表达。恢复的药物敏感性被认为受除DAPK外的未知甲基化调节分子的调节。DAPK敲低部分抑制cddp -抗性和vp16抗性，完全抑制5- fu抗性在部分汉布药成分中鉴定抗肿瘤药物的抗凋亡信号，建立耐药癌症的分子靶向治疗：在部分汉布药成分中鉴定出几种对抗癌药物具有较强抑制活性的分子（准备提交）。然后，进一步实验确定细胞内信号在抗凋亡现象中的作用。(1)汉布药成分刺激下细胞内信号通路的鉴定。MAPKK和DAPK可能与这些信号有一定的联系，目前正在调查中。mRNA谱分析和siRNA实验目前正在研究中。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