The oral protein-kinase C beta inhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines.
Deregulation of the protein kinase C (PKC) signalling pathway has been implicated in tumor progression. Here we investigated the PKC inhibitor enzastaurin for its activity against multiple myeloma (MM) cells. Enzastaurin suppresses cell proliferation in a large panel of human myeloma cell lines (HMCLs), with IC50 values ranging from 1.3 to 12.5 microM and induces apoptosis, which is prevented by the ZVAD-fmk broad caspase inhibitor. These results are consistent with decreased phosphorylation of AKT and GSK3-beta, a downstream target of the AKT pathway and a pharmacodynamic marker for enzastaurin. Furthermore, enzastaurin cytotoxicity is retained when HMCLs were cocultured with multipotent mesenchymal stromal cells. Enzastaurin has additive or synergistic cytotoxic effects with bortezomib or thalidomide. Considering the strong anti-myeloma activity of enzastaurin in vitro and in animal models and its safe toxicity profile, phase II studies in MM patients of enzastaurin alone or in combination with other drugs are warranted.
Neri
Antonino
A
Center of Molecular Genetics and Gene Expression, Foundation IRCCS Policlinico, Mangiagalli e Regina Elena, Italy.
Marmiroli
Sandra
S
Tassone
Pierfrancesco
P
Lombardi
Luigia
L
Nobili
Lucia
L
Verdelli
Donata
D
Civallero
Monica
M
Cosenza
Maria
M
Bertacchini
Jessika
J
Federico
Massimo
M
De Pol
Anto
A
Deliliers
Giorgio Lambertenghi
GL
Sacchi
Stefano
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D017154:Stromal Cells / Q000166:cytology
D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; C504878:enzastaurin