Connectivity map identifies HDAC inhibition as a treatment option of high-risk hepatoblastoma
| Autor: | Roland Kappler, Dietrich von Schweinitz, Alexander M. Beck, Beate Häberle, Christian Vokuhl, Michaela Hagemann, Stefano Cairo, Corinna Eberherr |
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| Rok vydání: | 2016 |
| Předmět: |
Hepatoblastoma
Male 0301 basic medicine Cancer Research Apoptosis Cell Growth Processes Biology Bioinformatics Histone Deacetylases 03 medical and health sciences 0302 clinical medicine Risk Factors Antineoplastic Combined Chemotherapy Protocols medicine Humans Viability assay Pharmacology Cisplatin Histone deacetylase 2 Liver Neoplasms Drug Synergism Hep G2 Cells medicine.disease HDAC1 Histone Deacetylase Inhibitors Regimen 030104 developmental biology Oncology Child Preschool 030220 oncology & carcinogenesis Cancer research Molecular Medicine Female Histone deacetylase Transcriptome Research Paper medicine.drug |
| Zdroj: | Cancer Biology & Therapy. 17:1168-1176 |
| ISSN: | 1555-8576 1538-4047 |
| DOI: | 10.1080/15384047.2016.1235664 |
| Popis: | Hepatoblastoma (HB) is the most common liver tumor of childhood, usually occurring in children under the age of 3 y. The prognosis of patients presenting with distant metastasis, vascular invasion and advanced tumor stages remains poor and children that do survive often face severe late effects from the aggressive chemotherapy regimen. To identify potential new therapeutics for high risk HB we used a 1,000-gene expression signature as input for a Connectivity Map (CMap) analysis, which predicted histone deacetylase (HDAC) inhibitors as a promising therapy option. Subsequent expression analysis of primary HB and HB cell lines revealed a general overexpression of HDAC1 and HDAC2, which has been suggested to be predictive for the efficacy of HDAC inhibition. Accordingly, treatment of HB cells with the HDAC inhibitors SAHA and MC1568 resulted in a potent reduction of cell viability, induction of apoptosis, reactivation of epigenetically suppressed tumor suppressor genes, and the reversion of the 16-gene HB classifier toward the more favorable expression signature. Most importantly, the combination of HDAC inhibitors and cisplatin – a major chemotherapeutic agent of HB treatment - revealed a strong synergistic effect, even at significantly reduced doses of cisplatin. Our findings suggest that HDAC inhibitors skew HB cells toward a more favorable prognostic phenotype through changes in gene expression, thus indicating a targeted molecular mechanism that seems to enhance the anti-proliferative effects of conventional chemotherapy. Thus, adding HDAC inhibitors to the treatment regimen of high risk HB could potentially improve outcomes and reduce severe late effects. |
| Databáze: | OpenAIRE |
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