3 years ago

Normal human immune cells are sensitive to telomerase inhibition by Brassica-derived 3,3-diindolylmethane,partly mediated via ERα/β-AP1 signaling

Normal human immune cells are sensitive to telomerase inhibition by Brassica-derived 3,3-diindolylmethane,partly mediated via ERα/β-AP1 signaling
Oliver Treeck, Johanna Gaus, Steffen Landerer, Corinna Herz, Nina Schlotz, Hoai Thi Thu Tran, Evelyn Lamy, Grace Akinyi Odongo, Lia Lehr, Ivan Skatchkov, Wolfgang R. Schäfer
Scope Indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) from Brassica plants are regarded as promising anticancer phytochemicals. The enzyme telomerase is a very attractive target for cancer therapeutics; in normal cells such as lymphocytes, it plays a decisive role for cell maintenance. The effect of I3C and DIM on telomerase in normal human immune cells (PBMC) was studied compared to leukaemia cells (HL-60). Signalling of telomerase regulation via estrogen receptor (ER) was addressed. Methods and results Short-term treatment with I3C and DIM inhibited telomerase activity in leukaemia cells (>30 μM I3C; >3 μM DIM). In CD3/CD28 activated PBMC, inhibition was stronger, though (>3 μM I3C; >1 μM DIM). DIM long-term treatment resulted in DNA damage induction and proliferation inhibition in PBMC as determined by the comet assay and CFSE staining, respectively. A relevance of ERα/β-AP1 signaling for telomerase inhibition on enzyme activity, but not transcription level became evident indicating a nonclassical mode for ER regulation of telomerase by DIM. Conclusion Although desired in cancer cells, this study identified a potential adverse impact of I3C and DIM on telomerase action in normal human immune cells, partly mediated by an ER-dependent mechanism. These new findings should be considered for potential chronic high-dose chemoprevention strategies using these compounds. 3,3′-diindolylmethane (DIM) and indole-3-carbinol from Brassica plants, promising anticancer phytochemicals, inhibit telomerase activity in leukemia cells but with higher sensitivity normal human immune cells. In immune cells this was found to be partly mediated by an estrogen-receptor dependent mechanism. Long-term treatment by DIM resulted in decreased proliferation and increased DNA damage. These new findings should be considered for potential chronic high-dose chemoprevention strategies using DIM.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/mnfr.201600524

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