The isothiocyanate erucin abrogates telomerase in hepatocellular carcinoma cells in vitro and in an orthotopic xenograft tumour model of HCC

Abstract

In contrast to cancer cells, most normal human cells have no or low telomerase levels which makes it an attractive target for anti-cancer drugs. The small molecule sulforaphane from broccoli is known for its cancer therapeutic potential in vitro and in vivo. In animals and humans it was found to be quickly metabolized into 4-methylthiobutyl isothiocyanate (MTBITC, erucin) which we recently identified as strong selective apoptosis inducer in hepatocellular carcinoma (HCC) cells. Here, we investigated the relevance of telomerase abrogation for cytotoxic efficacy of MTBITC against HCC. The drug was effective against telomerase, independent from TP53 and MTBITC also blocked telomerase in chemoresistant subpopulations. By using an orthotopic human liver cancer xenograft model, we give first evidence that MTBITC at 50 mg/KG b.w./d significantly decreased telomerase activity in vivo without affecting enzyme activity of adjacent normal tissue. Upon drug exposure, telomerase decrease was consistent with a dose-dependent switch to anti-survival, cell arrest and apoptosis in our in vitro HCC models. Blocking telomerase by the specific inhibitor TMPyP4 further sensitized cancer cells to MTBITC-mediated cytotoxicity. Overexpression of hTERT, but not enzyme activity deficient DNhTERT, protected against apoptosis; neither DNA damage nor cytostasis induction by MTBITC was prevented by hTERT overexpression. These findings imply that telomerase enzyme activity does not protect against MTBITC-induced DNA damage but impacts signalling processes upstream of apoptosis execution level.

The impact of cruciferous vegetable isothiocyanates on histone acetylation and histone phosphorylation in bladder cancer

“…We saw stronger HDAC inhibition by ECN than SFN, which is the most commonly studied of cruciferous vegetable phytochemical metabolites. Perhaps a stronger focus on ECN as a potential epigenetic modulator would be fruitful as it can be found at high concentrations in other cruciferous vegetables such as arugula [41, 42]. To the best of our knowledge, this is the first report of HDAC inhibition by erucin.…”

Allyl isothiocyanate induces replication-associated DNA damage response in NSCLC cells and sensitizes to ionizing radiation

“…p53 status) and epigenetic profiles. Moreover, ITCs were shown to exhibit their cytotoxic effects selectively towards tumor cells in several cancer models [ 23 , 24 ]. Consistent with these studies, both the ITCs exhibited growth inhibitory effects selectively towards cancer cells when compared with normal human bronchial epithelial cells (HBECs).…”

“…Moreover, numerous studies in human tumor xenograft models and tumor cell lines demonstrated tumor-specific growth inhibitory properties for ITCs [ 20 , 21 ]. Increasing evidence is also available for their ability to cause cell cycle arrest, induce apoptosis, suppress IκB and Nf-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling and binding to thiol-reactive groups of several cellular targets such as DNA topoisomerase 2, p53 and tubulins [ 18 , 21 , 22 , 23 ]. These studies strongly advocate for the existence of additional mechanisms that are independent from carcinogen detoxification for their cancer preventive properties.…”

Antioxidant effects of sulforaphane in human HepG2 cells and immortalised hepatocytes

“…In addition to the cytoprotective effect, SFN has also been shown to exhibit cytotoxic effects including promoting ER stress and cell death [11][12][13] ; disrupting mitochondria 14 , tubulin and microtubule function [15][16][17] ; inducing DNA damage 18 , apoptosis and cell cycle arrest [19][20][21][22] ; inhibiting telomerase activity 11,23 and protein-protein interaction in Hsp90 complex 24 . The complex bioactivities of SFN and subsequent cellular responses are highly dependent upon the dose and duration of SFN treatment.…”