GROWTH ARREST AND NON-APOPTOTIC CELL-DEATH ASSOCIATED WITH THE SUPPRESSION OF C-MYC EXPRESSION IN MCF-7 BREAST-TUMOR CELLS FOLLOWING ACUTE EXPOSURE TO DOXORUBICIN

In the MCF-7 human beast adenocarcinoma cell line, acute exposure to 1 mu M doxorubicin inhibited cell proliferation by similar to 75%. Anal ysis of cell cycle distribution indicated that within 24 hr, the G(2)/ M fraction increased more than 3-fold and the S-phase population decli ned by >50%. In addition to growth arrest, there was an similar to 40% reduction in the viable cell population after 72 kr. Gel electrophore tic resolution of low molecular weight DNA immediately after exposure of cells to doxorubicin failed to demonstrate ''laddered'' oligonucleo somal profiles associated with apoptosis. The absence of intracellular DNA fragments or release of fragmented DNA into the incubation medium was confirmed by spectrofluorophotometry over a 72 hr interval follow ing exposure of cells to 1 mu M doxorubicin. In addition, there was no evidence of the morphological features associated with apoptosis duri ng this period. Acute exposure to 1 mu M doxorubicin also produced a t ransient increase in c-myc message expression (within the first hour) followed by a decline to 70% of control levels within 2-4 hr. The redu ction in c-myc mRNA levels was concentration dependent and corresponde d closely with growth arrest (as well as with inhibition of DNA synthe sis). These findings (as well as similar reports demonstrating a corre spondence between reduced c-myc expression and growth inhibition by VM -26 and m-AMSA in MCF-7 cells) suggest that the down-regulation of c-m yc expression may reflect perturbations in regulatory processes contri buting to growth arrest in MCF-7 cells exposed to to topoisomerase II inhibitors.