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

Abstract

Enzastaurin (LY317615), an acyclic bisindolylmaleimide, is an oral inhibitor of the protein kinase CB 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 dexamethasonesensitive 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 Mmol/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 Mmol/L enzastaurin, IGF-I did not abrogate cell death induced with 3 Mmol/L enzastaurin. Moreover, enzastaurin-induced cell death was not affected by interleukin-6 or ZVAD-fmk. GSK3B 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]

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

“…Enzastaurin also reduced the phosphorylation of the downstream PKCb-signaling pathway effectors Akt and GSK3b; these findings are consistent with several previous reports in different cancer cell lines, xenografts and peripheral blood mononuclear cells (PBMCs) (Graff et al, 2005;Querfeld et al, 2006;Rizvi et al, 2006), suggesting the use of GSK3b phosphorylation in PBMCs as a pharmacodynamic marker for enzastaurin (Graff et al, 2005). Our experiments showed that the Akt pathway can also be affected by pemetrexed, as reported previously (Giovannetti et al, 2005(Giovannetti et al, , 2008.…”

“…Enzastaurin was originally evaluated in human tumour xenograft-bearing mice for its antiangiogenic activity upon PKCb inhibition, as it showed reduction of plasma VEGF levels together with a significant decrease in intratumoural vessel density (Keyes et al, 2004). However, several studies have shown that enzastaurin exhibits direct growth inhibiting effects on a wide array of cultured human tumour cells (Graff et al, 2005;Oberschmidt et al, 2005;Querfeld et al, 2006;Rizvi et al, 2006;Podar et al, 2007;Spalding et al, 2007;Lee et al, 2008). Recent studies suggest that the antitumour effects of enzastaurin are mediated through interference with the phosphatidylinositol 3-kinase (PI3K)/Akt pathway (Graff et al, 2005;Querfeld et al, 2006;Rizvi et al, 2006;Lee et al, 2008), an important pathway regulating the apoptotic response.…”

Specifying protein kinase C functions in melanoma

“…Enzastaurin also has direct effects on tumor cell growth, survival and invasion (Graff et al, 2005;Rizvi et al, 2006). Enzastaurin inhibited the growth of primary melanoma cultures and had a preferential growth inhibitory effect on uveal melanoma cell lines with GNAQ mutations (Hanauske et al, 2007;Wu et al, 2012).…”

Dual regulation of glucocorticoid-induced leucine zipper (GILZ) by the glucocorticoid receptor and the PI3-kinase/AKT pathways in multiple myeloma

“…Because glucocorticoids are potent inducers of apoptosis in myeloma cells, we screened additional MM chemotherapeutic agents including 2-methoxyestradiol, all-trans retinoic acid (ATRA), enzastaurin, rapamycin, and thalidomide to determine if GILZ up regulation was observed upon induction of apoptosis in myeloma cells by a variety of agents [37][38][39][40][41]. Despite inducing apoptosis in MM.1S cells, none of these drugs up regulated GILZ in our screen.…”