Induction of cell death by cytokines in cell cycle-synchronous tumor cell populations restricted to G(1) and G(2)

In the present work, cytokine-mediated induction of cell. death was investigated by flow cytometry in cell cycle-synchronous human tumor,cell populations gained by centrifugal elutriation or by cell cycle blockade with mimosine and aphidicolin. Attention was payed to the question of whether the effector phase of cell death takes place in the same phase of the cell cycle in which the death signal is received, Another point of interest was the question whether synchronization of cell populations with respect to the cell cycle leads to increased synchronicity of the death phase, The results demonstrate that supernatants from monocyte/tumor cell interaction cultures containing tumor necrosis factor-alpha, interferons, and interleukins-1 and -6 or appropriate combinations of pure cytokines cause cell cycle arrest predominantly in G(1) and to a lesser extent in G(2). Cell death is initiated from both arrest points. Cytokine-treated G(1) cells do not enter S phase, They die within the same G(1) phase in which they receive the death signal, In contrast, a high proportion of cytokine-treated G(2) cells pass through mitosis and are arrested and die in the subsequent G(1) phase, whereas only a smaller proportion of cells are arrested and die in G(2). The synchronicity of the death phase cannot be increased by the diverse methods of cell cycle synchronization applied, Interestingly, aurintricarboxylic acid, an agent known for inhibitory effects on nucleolytic activities and other protein/nucleic acid interactions, not only prevents cell death, but also cell cycle arrest. (C) 1996 Academic Press, Inc.