Molecular Preventive Medicine, Institute of Prevention and Cancer Epidemiology, University Medical Center Freiburg, Freiburg, Germany.
Institute of Environmental Health Sciences, University Medical Center Freiburg, Freiburg, Germany.
Mol Nutr Food Res. 2017 Sep;61(9). doi: 10.1002/mnfr.201600524. Epub 2017 Apr 6.
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.
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.
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.
植物来源的吲哚-3-甲醇（I3C）和 3,3'-二吲哚甲烷（DIM）被认为是有前途的抗癌植物化学物质。端粒酶是癌症治疗的一个非常有吸引力的靶点；在淋巴细胞等正常细胞中，它对细胞维持起着决定性的作用。本研究比较了 I3C 和 DIM 对正常人类免疫细胞（PBMC）和白血病细胞（HL-60）中端粒酶的影响。研究了端粒酶通过雌激素受体（ER）调节的信号。
I3C 和 DIM 的短期治疗抑制了白血病细胞中端粒酶的活性（>30 μM I3C；>3 μM DIM）。在 CD3/CD28 激活的 PBMC 中，尽管抑制作用更强，但是（>3 μM I3C；>1 μM DIM）。通过彗星试验和 CFSE 染色分别确定了 DIM 的长期处理导致 PBMC 中的 DNA 损伤诱导和增殖抑制。端粒酶抑制的酶活性而非转录水平的 ERα/β-AP1 信号的相关性表明 DIM 通过非经典途径调节端粒酶的 ER 作用。
尽管在癌细胞中是期望的，但本研究确定了 I3C 和 DIM 对正常人类免疫细胞中端粒酶作用的潜在不利影响，部分是通过 ER 依赖性机制介导的。这些新发现应考虑用于这些化合物的潜在慢性高剂量化学预防策略。
