ABSTRACT
Cytokine-induced killer (CIK) cells are a heterogeneous population of immune effector cells that feature a mixed T- and Natural killer (NK) cell-like phenotype in their terminally-differentiated CD3+CD56+ subset. The easy availability, high proliferation rate and widely major histocompatibility complex (MHC)-unrestricted antitumor activity of CIK cells contribute to their particularly advantageous profile, making them an attractive approach for adoptive immunotherapy. CIK cells have shown considerable cytotoxicity against both solid tumors and hematological malignancies in vitro and in animal studies. Recently, initial clinical experiences demonstrated the feasibility and efficacy of CIK cell immunotherapy in cancer patients, even at advanced disease stages. Likewise, the clinical application of CIK cells in combination with standard therapeutic procedures revealed synergistic antitumor effects. In this report, we will focus our consideration on CIK cells in the treatment of hematological malignancies. We will give insight into the latest advances and future perspectives and outline the most prominent results obtained in 17 clinical studies. Overall, CIK cells demonstrated a crucial impact on the treatment of patients with hematological malignancies, as evidenced by complete remissions, prolonged survival durations and improved quality of life. However, up to now, the optimal application schedule eventually favoring their integration into clinical practice has still to be developed.
Subject(s)
Cytokine-Induced Killer Cells/physiology , Hematologic Neoplasms/therapy , Immunotherapy, Adoptive/methods , Clinical Trials, Phase I as Topic , Cytokine-Induced Killer Cells/immunology , Hematologic Neoplasms/immunology , HumansABSTRACT
It was recently confirmed that the diuretic agent ethacrynic acid (EA) inhibits Wnt/beta catenin signaling in myeloma. This study investigated the antitumor effect of EA in vivo in a murine myeloma model. In vivo, tumor growth was significantly reduced and overall survival significantly prolonged in mice treated with EA as compared to untreated mice. Interestingly, this effect was higher as compared to the effect by lenalidomide, a commonly used drug against myeloma. These results reveal a significant in vivo effect by EA against myeloma.
Subject(s)
Diuretics/therapeutic use , Ethacrynic Acid/therapeutic use , Multiple Myeloma/drug therapy , Animals , Cell Line, Tumor , Disease Models, Animal , Drug Therapy, Combination , Ethacrynic Acid/administration & dosage , Humans , Lenalidomide , Mice , Mice, Inbred BALB C , Multiple Myeloma/mortality , Thalidomide/administration & dosage , Thalidomide/analogs & derivatives , Wnt Signaling Pathway , beta Catenin/physiologyABSTRACT
BACKGROUND: It was recently confirmed that ethacrynic acid (EA) inhibits Wnt/beta catenin signalling in myeloma. MATERIALS AND METHODS: This study investigated the antitumor effect of EA in vitro and in vivo in a murine myeloma model. RESULTS: EA demonstrated major apoptotic activity in different human and murine myeloma and lymphoma cell lines, as well as in human primary cells. In addition ß-catenin expression was down-regulated when EA was added to lymphoma cells. In vivo, tumor growth, as well as overall survival, was significantly reduced in mice treated with EA as compared to untreated mice. Interestingly, in vitro, a significant additive effect was seen with the combination of lenalidomide plus EA as compared to single applications. CONCLUSION: These results reveal a significant selective induction of apoptosis by EA and suggest a significant in vivo effect against myeloma.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Ethacrynic Acid/pharmacology , Thalidomide/analogs & derivatives , Thalidomide/pharmacology , Animals , Antibodies, Monoclonal, Murine-Derived/pharmacology , Boronic Acids/pharmacology , Bortezomib , Cell Line, Tumor , Cell Survival/drug effects , Dimethyl Sulfoxide/pharmacology , Doxorubicin/pharmacology , Drug Synergism , Female , Humans , Lenalidomide , Leukocytes, Mononuclear/drug effects , Lymphoma/metabolism , Mice , Mice, Inbred BALB C , Multiple Myeloma/metabolism , Pyrazines/pharmacology , Rituximab , Signal Transduction/drug effects , Wnt Proteins/metabolism , beta Catenin/metabolismABSTRACT
Recent studies have implicated genetic and epigenetic aberrations resulting in aberrant activation of the Wingless-Int (Wnt) pathway and thus influencing the initiation and progression of multiple myeloma (MM). Of major importance, these findings may lead to novel treatment strategies exploiting targeted modulation of Wnt signaling. This review describes the current status of knowledge concerning the role of Wnt pathway alteration in MM and outlines future lines of research and their clinical perspectives.
