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

Abstract

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 Cβ (PKCβ) 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 PKCβ1 and PKCβ2 isoforms was demonstrated in five B-ALL cell lines characterized by distinctive chromosomal translocations, and sensitivity to PKCβ-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 3β (GSK3β). These results indicate that PKCβ targeting should be considered as a potential treatment option in B-ALL.

Keywords:

• Acute lymphoblastic leukemia
• protein kinase Cβ
• targeted therapeutic
• apoptosis
• AKT
• GSK3β

Acknowledgements

The authors acknowledge with gratitude the support and mentorship of Drs. Hana Safah and Roy S. Weiner. The authors express gratitude to Dr. Tara Lin for sharing valuable materials, and acknowledge the excellent technical assistance of Adriana Zapata. This work was supported by grants to L.S. L. from the National Cancer Institute, NIH (R01 CA74731), the When Everyone Survives Foundation, and the Ladies Leukemia League, Inc., of the Gulf South Region.

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.