Cell cycle blockers mimosine, ciclopirox, and deferoxamine prevent the death of PC12 cells and postmitotic sympathetic neurons after removal of trophic support.
In the present study, we tested whether apoptotic neuronal death caused by withdrawal of trophic support might be prevented by agents that block cell cycle progression. We used three complementary model systems that exhibit apoptotic death: dividing PC12 cells deprived of nerve growth factor (NGF); and primary cultures of postmitotic sympathetic neurons deprived of NGF. We show that cell death in each case can be suppressed by treatment with the G1/S blockers mimosine, ciclopirox, and deferoxamine at concentrations that correlate with their abilities to block PC12 cell proliferation. In contrast, agents that block cell cycle progression in the S-, G2-, or M-phase do not prevent cell death. These observations support the hypothesis that removal of trophic support from dividing or postmitotic neuronal cells provokes their apoptotic death by causing them either to proceed through or to attempt to re-enter an uncoordinated and consequently fatal cell cycle. Moreover, the data suggest that simply blocking the cycle at any point is not protective but, rather, that it is necessary to block at specific "safe" points. This study defines a safe point in the cell cycle before the G1/S transition that is demarcated by the action of these three agents.
Farinelli
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SE
Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Greene
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LA
D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D000077768:Ciclopirox; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects*; D008898:Mimosine / Q000494:pharmacology*; D008938:Mitosis; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D015739:Nocodazole / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017783:Superior Cervical Ganglion / Q000166:cytology; D013713:Teniposide / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology
D009414:Nerve Growth Factors; D011728:Pyridones; D013873:Thionucleotides; D000077768:Ciclopirox; D016590:Aphidicolin; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D008898:Mimosine; D013713:Teniposide; D000242:Cyclic AMP; D003676:Deferoxamine; D015739:Nocodazole