Apoptotic induction in B-cell acute lymphoblastic leukemia cell lines treated with a protein kinase Cβ inhibitor

B-cell acute lymphoblastic leukemia (B-ALL) in adults exhibits a 5-year disease-free survival rate of only 25--40%% after currently available treatment. Protein kinase C beta beta (PKC beta beta) is under active consideration as a rational therapeutic target in several B-cell malignancies, but studies of its possible utility in B-ALL are lacking. Expression of PKC beta beta 1 and PKC beta beta 2 isoforms was demonstrated in five B-ALL cell lines characterized by distinctive chromosomal translocations, and sensitivity to PKC beta beta-selective inhibition was examined. Inhibitor treatment resulted in a dose-dependent reduction in viability in all cell lines, although pro-B ALL with t(4;11)(q21;q23) was most sensitive. Apoptotic induction was evident after 24--48 h of treatment, and an inhibition of cell cycle progression was detected in one cell line. Treatment resulted in a rapid induction of poly(ADP-ribose) polymerase (PARP) cleavage, indicating caspase-3-mediated apoptosis, and a rapid reduction in phosphorylation of AKT and its downstream target glycogen synthase kinase 3 beta beta (GSK3 beta beta). These results indicate that PKC beta beta targeting should be considered as a potential treatment option in B-ALL.</.