Abstract
In multiple myeloma (MM), protein kinase C (PKC) overexpression has been reported including the prognostic adverse patient group with t (4;14) translocation. Importantly, PKC signaling pathways have been implicated in MM cell proliferation, apoptosis, and migration. Here, we investigated the novel, orally available PKC inhibitor Enzastaurin for its anti-MM activity. Enzastaurin specifically inhibits membrane, cytosolic, and nuclear phosphorylation of homologous PKC isoform residues, as well as associated kinase activity, induced by the major PKC activator TPA (Tumor-promoting phorbol ester). Consequently, it also abrogates TPA-induced phosphorylation of signaling molecules downstream of PKC including MARCKS and PKCm. In MM, Enzastaurin inhibits PKC activation triggered by growth factors and cytokines secreted by bone marrow stromal cells (BMSCs); co-stimulation with the extracellular matrix protein fibronectin, VEGF or IL-6; as well as MM patient serum. Phosphorylation of downstream signaling molecules was also abrogated, including cytoplasmic and nuclear ERK, JNK, ribosomal protein S6 and GSK3b as well as nuclear cMyc. Enzastaurin inhibits both proliferation and survival of MM cell lines and MM cells isolated from multidrug- resistant patients; as well as overcomes MM cell growth triggered by tumor cell binding to BMSCs and endothelial cells at a low micromolar range equivalent to the concentrations achieved in patient plasma during clinical trials. Importantly, synergistic cytotoxicity is observed when Enzastaurin is combined with bortezomib. Besides proliferation and survival, Enzastaurin inhibits MM cell adhesion, as well as VEGF- and IGF-1-triggered MM cell migration. It also blocks VEGF- triggered signaling pathways in endothelial cells, thereby inhibiting tubule formation. Finally and most importantly, tumor growth, survival, and angiogenesis are abrogated by Enzastaurin in an in vivo xenograft model of human MM. Our results therefore demonstrate in vitro and in vivo efficacy of the orally available PKC inhibitor Enzastaurin in MM and strongly support its clinical evaluation, alone or in combination therapies, to improve patient outcome in MM.
Disclosure: No relevant conflicts of interest to declare.
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