Three structurally homologous isothiocyanates exert “Janus” characteristics in human HepG2 cells

Lamy, Evelyn; Crössmann, Catharina; Saeed, Adal; Schreiner, Peter R.; Kotke, Mike; Mersch-Sundermann, Volker

doi:10.1002/em.20470

Cited by 12 publications

(9 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ITC are comparatively electrophilic compounds that have been shown to act genotoxic, at least in vitro 1920. Representatively, the genotoxicity was investigated in terms of DNA break induction for 4-MTB-CN and benzyl-CN in comparison to benzyl-ITC using the Comet assay (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Cytotoxic and genotoxic potential of food-borne nitriles in a liver in vitro model

Kupke¹,

Herz

Hanschen

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

Isothiocyanates are the most intensively studied breakdown products of glucosinolates from Brassica plants and well recognized for their pleiotropic effects against cancer but also for their genotoxic potential. However, knowledge about the bioactivity of glucosinolate-borne nitriles in foods is very poor. As determined by GC-MS, broccoli glucosinolates mainly degrade to nitriles as breakdown products. The cytotoxicity of nitriles in human HepG2 cells and primary murine hepatocytes was marginal as compared to isothiocyanates. Toxicity of nitriles was not enhanced in CYP2E1-overexpressing HepG2 cells. In contrast, the genotoxic potential of nitriles was found to be comparable to isothiocyanates. DNA damage was persistent over a certain time period and CYP2E1-overexpression further increased the genotoxic potential of the nitriles. Based on actual in vitro data, no indications are given that food-borne nitriles could be relevant for cancer prevention, but could pose a certain genotoxic risk under conditions relevant for food consumption.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The single cell gel electrophoresis assay also known as Comet assay was carried out as described earlier with slight modifications20. The percent tail DNA and the Olive Tail Moment (OTM) were calculated as indicators of DNA damage.…”

Section: Methodsmentioning

confidence: 99%

Cytotoxic and genotoxic potential of food-borne nitriles in a liver in vitro model

Kupke¹,

Herz

Hanschen

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…4-methylthiobutyl isothiocyanate (MTBITC, erucin) was synthesized by the Inst. of Organic Chemistry, University of Giessen, Germany as described before [17].…”

Section: Methodsmentioning

confidence: 99%

The MAPK Pathway Signals Telomerase Modulation in Response to Isothiocyanate-Induced DNA Damage of Human Liver Cancer Cells

et al. 2013

Self Cite

View full text Add to dashboard Cite

4-methylthiobutyl isothiocyanate (MTBITC), an aliphatic, sulphuric compound from Brassica vegetables, possesses in vitro and in vivo antitumor activity. Recently we demonstrated the potent growth inhibitory potential of the DNA damaging agent MTBITC in human liver cancer cells. Here we now show that MTBITC down regulates telomerase which sensitizes cells to apoptosis induction. This is mediated by MAPK activation but independent from production of reactive oxygen species (ROS). Within one hour, MTBITC induced DNA damage in cancer cells correlating to a transient increase in hTERT mRNA expression which then turned into telomerase suppression, evident at mRNA as well as enzyme activity level. To clarify the role of MAPK for telomerase regulation, liver cancer cells were pre-treated with MAPK-specific inhibitors prior to MTBITC exposure. This clearly showed that transient elevation of hTERT mRNA expression was predominantly mediated by the MAPK family member JNK. In contrast, activated ERK1/2 and P38, but not JNK, signalled to telomerase abrogation and consequent apoptosis induction. DNA damage by MTBITC was also strongly abolished by MAPK inhibition. Oxidative stress, as analysed by DCF fluorescence assay, electron spin resonance spectroscopy and formation of 4-hydroxynonenal was found as not relevant for this process. Furthermore, N-acetylcysteine pre-treatment did not impact MTBITC-induced telomerase suppression or depolarization of the mitochondrial membrane potential as marker for apoptosis. Our data therefore imply that upon DNA damage by MTBITC, MAPK are essential for telomerase regulation and consequent growth impairment in liver tumor cells and this detail probably plays an important role in understanding the potential chemotherapeutic efficacy of ITC.

show abstract

“…4-methylthiobutyl isothiocyanate (MTBITC, erucin) was synthesized by the Inst. of Organic Chemistry, University of Giessen, Germany as described before [15]. Valinomycin was purchased from Fluka, (Buchs, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of 4-Methylthiobutyl Isothiocyanate on Liver Cancer and Cancer Stem Cells with Different p53 Status

et al. 2013

Self Cite

View full text Add to dashboard Cite

Isothiocyanates from plants of the order Brassicales are considered promising cancer chemotherapeutic phytochemicals. However, their selective cytotoxicity on liver cancer has been barely researched. Therefore, in the present study, we systematically studied the chemotherapeutic potency of 4-methylthiobutyl isothiocyanate (MTBITC). Selective toxicity was investigated by comparing its effect on liver cancer cells and their chemoresistant subpopulations to normal primary hepatocytes and liver tissue slices. Additionally, in a first assessment, the in vivo tolerability of MTBITC was investigated in mice. Growth arrest at G2/M and apoptosis induction was evident in all in vitro cancer models treated with MTBITC, including populations with cancer initiating characteristics. This was found independent from TP53; however cell death was delayed in p53 compromised cells as compared to wt-p53 cells which was probably due to differential BH3 only gene regulation i. e. Noxa and its antagonist A1. In normal hepatocytes, no apoptosis or necrosis could be detected after repeated administration of up to 50 µM MTBITC. In mice, orally applied MTBITC was well tolerated over 18 days of treatment for up to 50 mg/kg/day, the highest dose tested. In conclusion, we could show here that the killing effect of MTBITC has a definite selectivity for cancer cells over normal liver cells and its cytotoxicity even applies for chemoresistant cancer initiating cells. Our study could serve for a better understanding of the chemotherapeutic properties of isothiocyanates on human liver-derived cancer cells.

show abstract

Three structurally homologous isothiocyanates exert “Janus” characteristics in human HepG2 cells

Cited by 12 publications

References 39 publications

Cytotoxic and genotoxic potential of food-borne nitriles in a liver in vitro model

Cytotoxic and genotoxic potential of food-borne nitriles in a liver in vitro model

The MAPK Pathway Signals Telomerase Modulation in Response to Isothiocyanate-Induced DNA Damage of Human Liver Cancer Cells

Preclinical Evaluation of 4-Methylthiobutyl Isothiocyanate on Liver Cancer and Cancer Stem Cells with Different p53 Status

Contact Info

Product

Resources

About