title: 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.
authors.affiliation: Institute for Environmental Health Sciences and Hospital Infection Control, Freiburg University Medical Center, Freiburg, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Herz
authors.forename: Anke
authors.initials: A
authors.lastname: Hertrampf
authors.forename: Stefan
authors.initials: S
authors.lastname: Zimmermann
authors.forename: Nadine
authors.initials: N
authors.lastname: Stetter
authors.forename: Meike
authors.initials: M
authors.lastname: Wagner
authors.forename: Claudia
authors.initials: C
authors.lastname: Kleinhans
authors.forename: Miriam
authors.initials: M
authors.lastname: Erlacher
authors.forename: Julia
authors.initials: J
authors.lastname: Schüler
authors.forename: Stefanie
authors.initials: S
authors.lastname: Platz
authors.forename: Sascha
authors.initials: S
authors.lastname: Rohn
authors.forename: Volker
authors.initials: V
authors.lastname: Mersch-Sundermann
authors.forename: Evelyn
authors.initials: E
authors.lastname: Lamy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D017879:Isothiocyanates / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C587983:4-methylthiobutyl isothiocyanate; D000970:Antineoplastic Agents; D017879:Isothiocyanates; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D000077157:Sorafenib; D019098:Telomerase
keywords: 4-methylthiobutyl isothiocyanate/erucin; adjuvant chemotherapy; hTERT/telomerase suppression; hepatocellular carcinoma and chemoresistant subpopulations; sulforaphane