This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rizvi, M. A. Articles by Rosen, S. T. Search for Related Content PubMed PubMed Citation Articles by Rizvi, M. A. Articles by Rosen, S. T.

Research Articles: Therapeutics

Enzastaurin (LY317615), a protein kinase Cß inhibitor, inhibits the AKT pathway and induces apoptosis in multiple myeloma cell lines

¹ Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine and ² Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois

Requests for reprints: Mujahid A. Rizvi, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Lurie Building 3-250, 303 East Superior Street, Chicago, IL 60611. Phone: 312-695-6180; Fax: 312-695-6189. E-mail: m-rizvi{at}md.northwestern.edu

Enzastaurin (LY317615), an acyclic bisindolylmaleimide, is an oral inhibitor of the protein kinase Cß isozyme. The objective of this study was to assess the efficacy of enzastaurin in inducing apoptosis in multiple myeloma (MM) cell lines and to investigate possible mechanisms of apoptosis. Cell proliferation assays were done on a variety of MM cell lines with unique characteristics (dexamethasone sensitive, dexamethasone resistant, chemotherapy sensitive, and melphalan resistant). The dexamethasone-sensitive MM.1S cell line was used to further assess the effect of enzastaurin in the presence of dexamethasone, insulin-like growth factor-I (IGF-I), interleukin-6, and the pan-specific caspase inhibitor ZVAD-fmk. Enzastaurin increased cell death in all cell lines at clinically significant low micromolar concentrations (1–3 µmol/L) after 72 hours of treatment. Dexamethasone and enzastaurin were shown to have an additive effect on MM.1S cell death. Although IGF-I blocked the effect of 1 µmol/L enzastaurin, IGF-I did not abrogate cell death induced with 3 µmol/L enzastaurin. Moreover, enzastaurin-induced cell death was not affected by interleukin-6 or ZVAD-fmk. GSK3ß phosphorylation, a reliable pharmacodynamic marker for enzastaurin activity, and AKT phosphorylation were both decreased with enzastaurin treatment. These data indicate that enzastaurin induces apoptosis in MM cell lines in a caspase-independent manner and that enzastaurin exerts its antimyeloma effect by inhibiting signaling through the AKT pathway. [Mol Cancer Ther 2006;5(7):1783–9]

Received 11/ 8/05; revised 4/ 9/06; accepted 5/10/06.