INDUCTION OF APOPTOSIS BY THE ANTITUBULIN DRUG COLCEMID - RELATIONSHIP OF MITOTIC CHECKPOINT CONTROL TO THE INDUCTION OF APOPTOSIS IN HELA S3 CELLS

We have studied the relationship between apoptosis and drug-induced ce ll cycle perturbation in HeLa S3 cells when treated with the anti-tubu lin drug colcemid. We found that at least two distinct mechanisms cont ributed to colcemid cytotoxicity and apoptosis. Continuous exposure to concentrations of colcemid sufficient to block cells at the mitotic c heckpoint led to the appearance of apoptotic cells approximately one c ell cycle after their initial accumulation in mitosis. Continuous expo sure to concentrations sufficient to delay mitotic progression but ins ufficient to cause mitotic arrest, or pulse exposure to concentrations of colcemid sufficient to induce mitotic block, led to the generation of multipolar mitoses and genetically deficient hypodiploid daughter cells which underwent apoptosis while in interphase. The fact that abe rrant spindle function delayed but did not block cells at the mitotic checkpoint indicates that the mitotic checkpoint senses the presence o r absence of the spindle but not spindle abnormalities. In both mitoti c and interphase cells, colcemid-induced apoptosis occurred after a pe riod of cell cycle stasis during which cells failed to complete an ini tiated cell cycle. These results are discussed with reference to under standing the relationship between apoptosis and the regulation of cell cycle progression. (C) 1994 Academic Press, Inc.