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

将格尔达霉素（GA）应用于几种高表达HER-2的菌株，以确定GA作为一种hsp90选择性抑制剂是否可以作为一种分子靶向治疗卵巢癌。对于HER-2的中高表达，GA可导致蛋白表达降低，并明显抑制细胞增殖。另一方面，Hsp70与Hsp60等合作，对Hsp90发挥蛋白伴侣子功能。众所周知，Hsp70在卵巢、乳腺肿瘤和骨肉瘤等疾病中的表达会被夸大。与HER-2高表达的卵巢癌相比，我们对GA治疗组和对照组发生变化的蛋白组进行了蛋白质组学分析，发现与对照组相比，GA给药后Hsp70含量显著增加。推测GA使Hsp90从其与HSF-1（heat…More shock转录因子1）的结合中释放出来；HSF-1被激活，进而引起热休克蛋白基因的激活。换句话说，人们预计癌细胞会使Hsp70含量增加，以覆盖损伤，从而在抗肿瘤药物的攻击中存活下来。Hsp70的升高最终与这些细胞对凋亡的抵抗甚至耐药性的发展有关。目前，人们正在研究Hsp70作为分子伴侣的功能，以及其信号转导功能在细胞凋亡抑制中的作用，这一结果可能会导致一种新的主要针对卵巢癌的分子靶向治疗。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Hsp70参与蛋白水解的程度。还包括：发现在高表达Hsp70的菌株中加入Hsp70抑制剂是否能解决抗凋亡作用，最终克服抗肿瘤药物的耐药性。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