Perifosine and sorafenib combination induces mitochondrial cell death and antitumor effects in NOD/SCID mice with Hodgkin lymphoma cell line xenografts

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 pro...

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Veröffentlicht in:	Leukemia 2013-08, Vol.27 (8), p.1677-1687
Hauptverfasser:	Locatelli, S L, Giacomini, A, Guidetti, A, Cleris, L, Mortarini, R, Anichini, A, Gianni, A M, Carlo-Stella, C
Format:	Artikel
Sprache:	eng
Schlagworte:	631/154/436/2388 631/67/1059 631/67/1990/291/1556 AKT protein Animals Anticancer properties Antineoplastic Combined Chemotherapy Protocols Antitumor activity Apoptosis Apoptosis - drug effects Cancer Research Caspases - metabolism CD30 antigen Cell cycle Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell death Cell Line, Tumor Cell Proliferation - drug effects Chemotherapy Clinical trials Cluster Analysis Combined treatment Critical Care Medicine DNA biosynthesis Drug dosages Drug Synergism Drug therapy Drug therapy, Combination Extracellular signal-regulated kinase Gene Expression Profiling Gene Expression Regulation, Neoplastic - drug effects Growth factors Hematology Hodgkin Disease - drug therapy Hodgkin Disease - genetics Hodgkin Disease - metabolism Hodgkin Disease - pathology Hodgkin's disease Hodgkin's lymphoma Homology In vivo methods and tests Intensive Internal Medicine Kinases Leukemia Lymphoma MAP kinase Medicine Medicine & Public Health Methods Mice Mice, Inbred NOD Mice, SCID Mitochondria Mitochondria - drug effects Mitochondria - metabolism Mitogen-Activated Protein Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinases - metabolism Mortality Necrosis Niacinamide - administration & dosage Niacinamide - analogs & derivatives Niacinamide - pharmacology Oncology original-article Patient outcomes Phenylurea Compounds - administration & dosage Phenylurea Compounds - pharmacology Phosphorylation Phosphorylcholine - administration & dosage Phosphorylcholine - analogs & derivatives Phosphorylcholine - pharmacology Protein kinase Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Raf protein Signal Transduction - drug effects Software Transcription Transplants & implants Tumor Burden - drug effects Tumor cell lines Tumors Xenograft Model Antitumor Assays Xenografts Xenotransplantation
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Zusammenfassung:	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
ISSN:	0887-6924 1476-5551
DOI:	10.1038/leu.2013.28