Direct and natural killer cell-mediated antitumor effects of low-dose bortezomib in hepatocellular carcinoma
| Autor: | Thomas S. Weiss, Alexander Steinle, Michael Bitzer, Ulrich M. Lauer, Matthias Krusch, Helmut R. Salih, Katrin M. Baltz, Irina Smirnow, S. Armeanu |
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| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Carcinoma Hepatocellular Cell Fluorescent Antibody Technique Antineoplastic Agents Biology GPI-Linked Proteins Natural killer cell Bortezomib Interleukin 21 Interferon-gamma Cell Line Tumor medicine Humans Cytotoxicity Cell Proliferation Lymphokine-activated killer cell Reverse Transcriptase Polymerase Chain Reaction Histocompatibility Antigens Class I Liver Neoplasms Flow Cytometry Boronic Acids Killer Cells Natural medicine.anatomical_structure Oncology Cell culture Pyrazines Immunology Cancer research Proteasome inhibitor Intercellular Signaling Peptides and Proteins medicine.drug |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 14(11) |
| ISSN: | 1078-0432 |
| Popis: | Purpose: Hepatocellular carcinoma (HCC) displays particular resistance to conventional cytostatic agents. Alternative treatment strategies focus on novel substances exhibiting antineoplastic and/or immunomodulatory activity enhancing for example natural killer (NK) cell antitumor reactivity. However, tumor-associated ligands engaging activating NK cell receptors are largely unknown. Exceptions are NKG2D ligands (NKG2DL) of the MHC class I-related chain and UL16-binding protein families, which potently stimulate NK cell responses. We studied the consequences of proteasome inhibition with regard to direct and NK cell–mediated effects against HCC. Experimental Design: Primary human hepatocytes (PHH) from different donors, hepatoma cell lines, and NK cells were exposed to Bortezomib. Growth and viability of the different cells, and immunomodulatory effects including alterations of NKG2DL expression on hepatoma cells, specific induction of NK cell cytotoxicity and IFN-γ production were investigated. Results: Bortezomib treatment inhibited hepatoma cell growth with IC50 values between 2.4 and 7.7 nmol/L. These low doses increased MICA/B mRNA levels, resulting in an increase of total and cell surface protein expression in hepatoma cells, thus stimulating cytotoxicity and IFN-γ production of cocultured NK cells. Importantly, although NK cell IFN-γ production was concentration-dependently reduced, low-dose Bortezomib neither induced NKG2DL expression or cell death in PHH nor altered NK cell cytotoxicity. Conclusions: Low-dose Bortezomib mediates a specific dual antitumor effect in HCC by inhibiting tumor cell proliferation and priming hepatoma cells for NK cell antitumor reactivity. Our data suggest that patients with HCC may benefit from Bortezomib treatment combined with immunotherapeutic approaches such as adoptive NK cell transfer taking advantage of enhanced NKG2D-mediated antitumor immunity. |
| Databáze: | OpenAIRE |
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