EARLY INDUCTION OF APOPTOSIS IN HEMATOPOIETIC-CELL LINES AFTER EXPOSURE TO FLAVOPIRIDOL

Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor models in vivo. While surveying the effect of flavopiridol on cell cyc le progression in different cell types, we discovered that hematopoiet ic cell lines, including SUDHL4, SUDHL6 (B-cell lines), Jurkat, and MO LT4 (T-cell lines), and HL60 (myeloid), displayed notable sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 1 2 hours, SUDHL4 cells displayed a similar degree of DNA fragmentation to that shown by the apoptosis-resistant PC3 prostate carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to 1,000 nmol/L f lavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells despite compara ble potency (SUDHL4:120 nmol/L; PC3: 203 nmol/L) in causing growth inh ibition by 50% (IC50). Flavopiridol did not induce topoisomerase I or II cleavable complex activity. A relation of p53, bcl2, or bar protein levels to apoptosis in SUDHL4 was not appreciated. While flavopiridol caused cell cycle arrest with decline in CDK1 activity in PC3 cells, apoptosis of SUDHL4 cells occurred without evidence of cell cycle arre st. These results suggest that antiproliferative activity of flavopiri dol (manifest by cell cycle arrest) may be separated in different cell types from a capacity to induce apoptosis. Cells from hematopoietic n eoplasms appear in this limited sample to be very susceptible to flavo piridol-induced apoptosis and therefore clinical trials in hematopoiet ic neoplasms should be of high priority. (C) 1998 by The American Soci ety of Hematology.