Biological significance of apoptosis signals and survival signals on radiosensitivity.

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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.