A trial at developing molecular-targeted therapy of ovarian cancer using a molecular chaperon heat shock protein(Hsp) as the target

为了探讨Hsp90选择性抑制物格尔达霉素(GA)能否作为一种分子靶向治疗卵巢癌的药物，对多种HER-2高表达的细胞株给予格尔达那霉素(GA)。对于HER-2的中高表达，GA处理后HER-2蛋白表达减少，细胞增殖受到明显抑制。另一方面，Hsp70与Hsp60等协同发挥Hsp90的蛋白伴侣功能。已知Hsp70的表达在卵巢、乳腺肿瘤和骨肉瘤等疾病中被夸大。我们对GA处理组和对照组发生变化的蛋白质组进行了蛋白质组学分析，并与高表达HER-2的卵巢癌进行了比较，发现GA处理后HSP70的含量显著高于对照组。据推测，GA管理部门从其与HSF-1(热…)的结合中释放了HSP90更多的休克转录因子1)；HSF-1被激活，进而导致HSP基因激活。换句话说，人们预计癌细胞会导致Hsp70含量增加，以弥补损害，以努力在抗肿瘤药物注射的冲击下生存下来。Hsp70的增加最终与这些细胞对凋亡的抵抗甚至与耐药性的发展有关。目前，人们不仅在研究Hsp70作为分子伴侣的功能，而且还在研究其在抑制细胞凋亡中的信号转导功能，以期为卵巢癌提供一种新的分子靶向治疗方法。目前，正在进行一项研究，通过制备Hsp70的RNAi并将该基因导入细胞来评估Hsp70参与蛋白质降解的程度。还包括：发现在高表达Hsp70的菌株中添加Hsp70抑制剂是否会解决抗凋亡作用，并最终克服对抗肿瘤药物的耐药性。较少

Geldanamycin(GA) was administered to several strains highly expressive of various HER-2 to find whether GA, an Hsp90-selective inhibitor, can be administered to ovarian cancer as a molecular-targeted therapy. For a medium-to-high degree of expression of HER-2, GA administration resulted in a reduction in protein expression and an evident suppression of cell proliferation. On the other hand, Hsp70, in cooperation with Hsp60 and others, performed a protein chaperon function for Hsp90. It has been known that Hsp70 expression is exaggerated in conditions such as ovarian and breast tumors and osteosarcoma. We have conducted a proteomics analysis of the protein group that had undergone changes in the Ga-treated and control groups, in comparison with the ovarian cancer with high HER-2 expression, and learned that the Hsp70 content increased significantly after GA administration, in comparison with the control. It was presumed that GA administration releases Hsp90 from its bond with HSF-1(heat … More shock transcription factor 1) ; HSF-1 is activated, in turn causing the Hsp gene activation. In other words, one expects that the cancer cells cause the Hsp70 content to increase to cover the damage, in an effort to survive the onslaught by antineoplastic agent administration. The increase in Hsp70 is ultimately linked to the resistance to apoptosis and even to the development of drug resistance of these cells. Currently, a study is underway not only on the Hsp70 function as a molecular chaperon but also on its signal transduction function in apoptosis-suppressive effects so that the results may lead to a new molecular targeted therapy mainly for ovarian cancer. Currently, a study is being conducted to evaluate the extent of involvement of Hsp70 in proteolysis by preparing RNAi of Hsp70 and introducing the gene into the cells. Also included : to discover whether the addition of an Hsp70 inhibitor to a strain with a high expression of Hsp70 will resolve the anti-apoptosis action and ultimately result in overcoming the resistance to antineoplastic agents. Less