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Epigenetic priming of non-small cell lung cancer cell lines to the antiproliferative and differentiating effects of all-trans retinoic acid

  • Original Article – Cancer Research
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Abstract

Purpose

The retinoic acid signaling pathway, crucial for differentiation, is silenced by epigenetic mechanisms in many cancers. Epigenetically active, chromatin-modifying agents offer a novel treatment approach, by reactivating aberrantly silenced genes in tumor cells and by sensitizing them to subsequent treatments. We hypothesized that the treatment of non-small cell lung cancer (NSCLC) cells with a histone deacetylase (HDAC) inhibitor may prime them to the antiproliferative and differentiating activity of all-trans retinoic acid.

Methods

The NSCLC cell lines A549, NCI-H460 and HCC827 were treated with ATRA (2 µM) and the pan-HDAC inhibitor panobinostat (LBH589; 10–35 nM).

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 p21CIP1/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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Acknowledgments

We thank Tobias Ma for technical assistance and Gregor Klaus, Dr. Nadja Blagitko-Dorfs, Dr. Milena Pantic, Dr. Ralph Fritsch and Dr. Dietmar Pfeifer for helpful discussions. This work was supported by the German Research Foundation (DFG, CRC 992 MEDEP, Project C-04).

Conflict of interest

The authors have no potential conflicts of interest.

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Correspondence to Michael Lübbert.

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Greve, G., Schiffmann, I. & Lübbert, M. Epigenetic priming of non-small cell lung cancer cell lines to the antiproliferative and differentiating effects of all-trans retinoic acid. J Cancer Res Clin Oncol 141, 2171–2180 (2015). https://doi.org/10.1007/s00432-015-1987-1

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  • DOI: https://doi.org/10.1007/s00432-015-1987-1

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