Peripheral benzodiazepine receptor ligands induce apoptosis and cell cycle arrest in human hepatocellular carcinoma cells and enhance chemosensitivity to paclitaxel, docetaxel, doxorubicin and the Bcl-2 inhibitor HA14-1
| Autor: | Rajan Somasundaram, Michael Höpfner, Detlef Schuppan, Bernhard Heine, Kerstin Maaser, Harald Stein, Martin Zeitz, Antje Krahn, Gesine Bradacs, Hans Scherübl, Kirsten Vormbrock, Patricia Grabowski, Andreas P. Sutter |
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| Rok vydání: | 2004 |
| Předmět: |
PK-11195
Carcinoma Hepatocellular Cell cycle checkpoint Paclitaxel bcl-X Protein Antineoplastic Agents Apoptosis Docetaxel Pharmacology Ligands Tritium chemistry.chemical_compound Bcl-2-associated X protein Cell Line Tumor Nitriles medicine Humans Benzopyrans Doxorubicin RNA Messenger Enzyme Inhibitors neoplasms bcl-2-Associated X Protein Antibiotics Antineoplastic Hepatology biology Cell Cycle Liver Neoplasms Drug Synergism Cell cycle Isoquinolines Receptors GABA-A Antineoplastic Agents Phytogenic digestive system diseases Proto-Oncogene Proteins c-bcl-2 chemistry biology.protein Taxoids Cell Division medicine.drug |
| Zdroj: | Journal of Hepatology. 41:799-807 |
| ISSN: | 0168-8278 |
| Popis: | Background/Aims Hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths worldwide. Thus, novel therapies are urgently needed. A promising approach is the use of peripheral benzodiazepine receptor (PBR) ligands which inhibit the proliferation of various tumors. Methods PBR expression both in human HCC cell lines and in tumor specimens of HCC patients was analyzed by RT-PCR and immunostaining. To evaluate PBR ligands for the treatment of HCC, we tested their effects on human HCC cells. Results PBR was localized to the mitochondria both of HCC cell lines and tumor tissues of HCC patients. In contrast, normal liver did not express PBR. PBR ligands inhibited the proliferation of HCC cell lines by inducing apoptosis and cell cycle arrest. Apoptosis was characterized by a breakdown of the mitochondrial membrane potential, caspase-3 activation and nuclear degradation. Furthermore, pro-apoptotic Bax was overexpressed while anti-apoptotic Bcl-2 and Bcl-X L were suppressed. Cell cycle was arrested both at the G1/S- and G2/M-checkpoints. Synergistic anti-neoplastic effects were obtained by a combination of PBR ligands with cytostatic drugs (paclitaxel, docetaxel, doxorubicin), or with an experimental Bcl-2 inhibitor. Conclusions This is the first report on the induction of apoptosis and cell cycle arrest by PBR ligands in HCC cells. Moreover, PBR ligands sensitized HCC cells to taxans and doxorubicin. |
| Databáze: | OpenAIRE |
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