Phorbol esters can protect mouse pre-T cell lines from radiation-induced rapid interphase apoptosis

Protein kinase C stimulators were found to increase the radioresistance of the mouse pre-T cell-derived line ST4. Increased resistance to gamma-ray-induced killing could be produced by addition of 10 nM phorbol 12-myristate 13-acetate (PMA) to ST4 cultures either immediately before or up to 2 h after irradiation. Following PMA treatment, ST4 changed from a cell line that underwent rapid interphase apoptosis (i.e. DNA degradation and morphology characteristic of apoptosis were evident 2-3 h after irradiation) to a line that continued to cycle after irradiation and began to die by apoptosis after completing mitosis. Associated with these PMA-induced changes, the D0 of ST4 cells increased from 7.7 +/- 0.7 to 18.8 +/- 2.7 125I decays. Another mouse pre-T cell-derived line, ST1, which is susceptible to radiation-induced rapid interphase apoptosis, also showed radioprotection after PMA treatment. In contrast, PMA increased the radiosensitivity of the pre-T cell-derived W7 line, which undergoes radiation-induced delayed interphase apoptosis (i.e. death following blockage in G2 phase). PMA had no effect on the radiosensitivity of a pre-B cell-derived line, A8, which undergoes rapid interphase apoptosis, and on a pre-T cell-derived line, W22, which undergoes apoptosis after mitosis. These results suggest that the radiomodifying ability of PMA treatment is dependent upon the cell death pathway induced by irradiation and upon the cell lineage.