Abstract
The effects of the Akt inhibitor perifosine and the RAF/MEK/ERK inhibitor sorafenib were investigated using two CD30(+)Hodgkin lymphoma cell lines (L-540 and HDLM-2) and the CD30(-)HD-MyZ histiocytic cell line. The combined perifosine/sorafenib treatment significantly inhibited mitogen-activated protein kinase and Akt phosphorylation in two of the three cell lines. Profiling of the responsive cell lines revealed that perifosine/sorafenib decreased the amplitude of transcriptional signatures that are associated with the cell cycle, DNA replication and cell death. Tribbles homolog 3 (TRIB3) was identified as the main mediator of the in vitro and in vivo antitumor activity of perifosine/sorafenib. Combined treatment compared with single agents significantly suppressed cell growth (40-80%, P<0.001), induced severe mitochondrial dysfunction and necroptotic cell death (up to 70%, P<0.0001) in a synergistic manner. Furthermore, in vivo xenograft studies demonstrated a significant reduction in tumor burden (P<0.0001), an increased survival time (81 vs 45 days, P<0.0001), an increased apoptosis (2- to 2.5-fold, P<0.0001) and necrosis (2- to 8-fold, P<0.0001) in perifosine/sorafenib-treated animals compared with mice receiving single agents. These data provide a rationale for clinical trials using perifosine/sorafenib combination.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Combined Chemotherapy Protocols
-
Apoptosis / drug effects*
-
Caspases / metabolism
-
Cell Cycle Proteins / genetics
-
Cell Cycle Proteins / metabolism
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Cluster Analysis
-
Drug Synergism
-
Gene Expression Profiling
-
Gene Expression Regulation, Neoplastic / drug effects
-
Hodgkin Disease / drug therapy
-
Hodgkin Disease / genetics
-
Hodgkin Disease / metabolism*
-
Hodgkin Disease / pathology
-
Mice
-
Mice, Inbred NOD
-
Mice, SCID
-
Mitochondria / drug effects*
-
Mitochondria / metabolism
-
Mitogen-Activated Protein Kinases / antagonists & inhibitors
-
Mitogen-Activated Protein Kinases / metabolism
-
Necrosis
-
Niacinamide / administration & dosage
-
Niacinamide / analogs & derivatives*
-
Niacinamide / pharmacology
-
Phenylurea Compounds / administration & dosage
-
Phenylurea Compounds / pharmacology*
-
Phosphorylcholine / administration & dosage
-
Phosphorylcholine / analogs & derivatives*
-
Phosphorylcholine / pharmacology
-
Protein Kinase Inhibitors / administration & dosage
-
Protein Kinase Inhibitors / pharmacology
-
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
-
Proto-Oncogene Proteins c-akt / metabolism
-
Signal Transduction / drug effects
-
Sorafenib
-
Tumor Burden / drug effects
-
Xenograft Model Antitumor Assays
Substances
-
Cell Cycle Proteins
-
Phenylurea Compounds
-
Protein Kinase Inhibitors
-
TRB3 protein, mouse
-
Phosphorylcholine
-
Niacinamide
-
perifosine
-
Sorafenib
-
Proto-Oncogene Proteins c-akt
-
Mitogen-Activated Protein Kinases
-
Caspases