THE NOVEL CYCLIN-DEPENDENT KINASE INHIBITOR FLAVOPIRIDOL DOWN-REGULATES BCL-2 AND INDUCES GROWTH ARREST AND APOPTOSIS IN CHRONIC B-CELL LEUKEMIA LINES

Flavopiridol is a novel, potent inhibitor of cyclin-dependent kinases (CDK). This synthetic flavone has been reported to exhibit antitumor a ctivity in murine and human tumor cell lines in vitro and in vivo and is currently undergoing clinical phase I evaluation. In the present st udy, 1 Epstein-Barr virus (EBV)-transformed B-prolymphocytic cell line (JVM-2), 1 EBV-transformed B-CLL cell line (I83CLL), and 1 non-EBV tr ansformed B-CLL cell line (WSU-CLL) were used as targets. Treatment of the cells with flavopiridol (100 nmol/L to 400 nmol/L) led to a marke d dose-and time-dependent inhibition of cell growth and survival as de termined using trypan blue exclusion. Morphologic analysis showed char acteristic apoptotic changes such as chromatin condensation and fragme ntation, membrane blebbing, and formation of apoptotic bodies. Further more, quantitative assessment of apoptosis-associated DNA strand break s by in situ TdT labeling showed that a significant number of flavopir idol-treated cells underwent apoptosis. These cellular effects were as sociated with a significant decrease in bcl-2 expression as observed b y Northern and Western blotting. The results showed that flavopiridol downregulates bcl-2 mRNA and bcl-2 protein expression within 24 hours. Genistein and quercetin, two flavonoids that do not inhibit CDKs, did not affect bcl-2 expression. These data suggest an additional mechani sm of action of this new flavone which might be useful as an agent in the treatment of chronic lymphoid malignancies. (C) 1997 by The Americ an Society of Hematology.