Biological significance of apoptosis signals and survival signals on radiosensitivity.

1.通过阻断生存信号转导途径的放射增敏作用酪氨酸激酶抑制剂染料木黄酮与放射联用可大大增强放射增敏作用。辐射激活ERK和Akt，尽管p53的状态，但染料木素与辐射的组合很好地抑制辐射诱导的ERK和Akt的激活。与抑制一致，细胞周期蛋白D表达降低，尤其是在TE-1中。染料木黄酮还增强了具有野生型p53的细胞中的辐射诱导的凋亡。相反，在具有突变型p53的细胞中未观察到PARP裂解的增加。EGF受体特异性激酶抑制剂AG 1478、Mek抑制剂PD 98059和P13 K抑制剂LY 29002也表现出协同作用。AG 1478、PD 98059和LY 294002对野生型p53细胞的放射增敏作用明显强于突变型p53细胞，但对染料木素无明显影响。2.其他放射增敏作用的分子靶点1）Radicicol、Hsp 90伴侣复合物抑制剂对突变型p53细胞也有放射增敏作用，并诱导辐射诱导的凋亡。2）曲古抑菌素A、HDAC抑制剂可增强p53野生型和突变型细胞的放射敏感性，并以非p53依赖的方式增加辐射诱导的细胞凋亡。通过破坏Raf-1与Hsp 90的结合而使Raf-1降解可能涉及强调放射敏感性增强的机制。

1. Radiosensitization by blockade of survival signal transduction pathwaysTyrosine kinase inhibitor, genistein, in combination with radiation greatly enhanced radiosensitivity. Radiation activated ERK and Akt in spite of p53 status, but genistein in combination with radiation well inhibited radiation-induced activation of ERK and Akt. In consistent with inhibition, cyclin D expression decreased especially in TE-1. Genistein also enhanced radiation induced apoptosis in cells that has wild type p53. In contrast, no increase in PARP cleavage was observed in cells that has mutant p53. AG1478, EGF receptor specific kinase inhibitor, PD98059, Mek inhibitor, and LY29002, P13K inhibitor also exhibited synergistic effect. AG1478, PD98059 and LY294002 enhanced radiosensitivities of cells with wild type p53 more predominantly than cell with mutant type p53 but not by genistein.2.Other molecular targets for radiosensitization1)Radicicol, Hsp90 chaperon complex inhibitor demonstrated radiosensitizing effects and induced radiation-induced apoptosis even in cells with mutant type p53. Blockade of radiarion-induced activation of p42/p44 by radicicol was considered to be a possible mechanism of radiosensitization.2)Trichostatin A, HDAC inhibitors enhanced radiosensitivity in both cell lines with wild type and mutant type p53, accompanying increase in radiation-induced apoptosis in a p53 independent manner. Raf-1 degradation through disruption of the binding of Raf-1 to Hsp90 may be involved in underlining mechanism of enhancement of radiosensitivity.