Abstract | PURPOSE: METHODS: RESULTS: While treatment with ATRA alone showed only very modest effects, panobinostat reduced cellular proliferation by at least 50 %. Notably, the combination of panobinostat and ATRA had additive and synergistic effects, respectively, on growth inhibition and differentiation, with almost no cytotoxicity. Effects were strongest in A549, followed by the EGFR-mutant HCC827, and least pronounced in NCI-H460. Global histone H3 acetylation was strongly induced by panobinostat; interestingly, ATRA alone had also an effect on histone acetylation, which was synergistically enhanced when the HDAC inhibitor was added. The combination of the two drugs additively decreased expression of phospho-ERK and phospho-AKT, whereas p53 and p21(CIP1/WAF1) proteins were both induced. CONCLUSION:
Panobinostat sensitized, to varying degrees, all three cell lines to the antiproliferative and differentiating effects of ATRA, with synergistic histone H3 acetylation. Combination therapy with an epigenetic drug and ATRA may offer an alternative to aggressive chemotherapy even in primary ATRA-insensitive tumors, such as adenocarcinomas of the lung.
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Authors | Gabriele Greve, Insa Schiffmann, Michael Lübbert |
Journal | Journal of cancer research and clinical oncology
(J Cancer Res Clin Oncol)
Vol. 141
Issue 12
Pg. 2171-80
(Dec 2015)
ISSN: 1432-1335 [Electronic] Germany |
PMID | 26008188
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Biomarkers, Tumor
- Histones
- Tretinoin
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Topics |
- Acetylation
- Adenocarcinoma
(drug therapy, genetics, pathology)
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Biomarkers, Tumor
(metabolism)
- Blotting, Western
- Carcinoma, Large Cell
(drug therapy, genetics, pathology)
- Carcinoma, Non-Small-Cell Lung
(drug therapy, genetics, pathology)
- Cell Differentiation
(drug effects)
- Cell Proliferation
(drug effects)
- Epigenesis, Genetic
(drug effects)
- Histones
(genetics, metabolism)
- Humans
- Lung Neoplasms
(drug therapy, genetics, pathology)
- Signal Transduction
(drug effects)
- Tretinoin
(pharmacology)
- Tumor Cells, Cultured
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