Effects of enzastaurin, alone or in combination, on signaling pathway controlling growth and survival of B-cell lymphoma cell lines.

Immunochemotherapies have improved outcomes in indolent lymphoma. However, response durations progressively shorten following each treatment, and the majority of patients eventually die from the disease. Thus, new, less toxic, and more active treatments are needed. Protein kinase C (PKC), which has been repeatedly implicated in B-cell lymphoma progression, may be a new target for lymphoma cell growth inhibition. Enzastaurin, a PKC-beta inhibitor, has toxic effects on a variety of cancer cells. The purpose of the present study was to assess the antitumor activity of enzastaurin on B-cell lymphoma cell lines and to investigate the underlying antitumor mechanisms. Enzastaurin induced apoptosis and inhibited phosphorylation of PKC, RSK, AKT, and downstream proteins. Moreover, our results reveal a new mechanism for enzastaurin-induced apoptosis via BAD activation. Finally, enzastaurin synergizes in its effects with chlorambucil and fludarabine, respectively. Taken together, our results strongly support clinical evaluation of enzastaurin in patients with B-cell lymphoma.