Back to Search
Start Over
Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl)
- Source :
- Blood. 109:1669-1677
- Publication Year :
- 2006
- Publisher :
- American Society of Hematology, 2006.
-
Abstract
- In multiple myeloma (MM) protein kinase C (PKC) signaling pathways have been implicated in cell proliferation, survival, and migration. Here we investigated the novel, orally available PKC-inhibitor enzastaurin for its anti-MM activity. Enzastaurin specifically inhibits phorbol ester–induced activation of PKC isoforms, as well as phosphorylation of downstream signaling molecules MARCKS and PKCμ. Importantly, it also inhibits PKC activation triggered by growth factors and cytokines secreted by bone marrow stromal cells (BMSCs), costimulation with fibronectin, vascular endothelial growth factor (VEGF), or interleukin-6 (IL-6), as well as MM patient serum. Consequently, enzastaurin inhibits proliferation, survival, and migration of MM cell lines and MM cells isolated from multidrug-resistant patients and overcomes MM-cell growth triggered by binding to BMSCs and endothelial cells. Importantly, strong synergistic cytotoxicity is observed when enzastaurin is combined with bortezomib and moderate synergistic or additive effects when combined with melphalan or lenalidomide. Finally, 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 outcome in patients with MM.
- Subjects :
- Indoles
Angiogenesis
medicine.medical_treatment
Transplantation, Heterologous
Immunology
Administration, Oral
Cell Communication
Biochemistry
Mice
chemistry.chemical_compound
Drug Delivery Systems
Enzastaurin
In vivo
Phorbol Esters
Lymphocyte costimulation
Tumor Cells, Cultured
Animals
Humans
Protein Isoforms
Medicine
Phosphorylation
Protein Kinase C
Protein kinase C
Neovascularization, Pathologic
Neoplasia
business.industry
Bortezomib
Growth factor
Cell Biology
Hematology
Coculture Techniques
Tumor Burden
Cell biology
Enzyme Activation
Vascular endothelial growth factor A
chemistry
Cancer research
Cytokines
Stromal Cells
Multiple Myeloma
business
medicine.drug
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 109
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....a1f5400275eefaca14ca8da8b825d451