Open AccessThe isothiocyanate erucin abrogates telomerase in hepatocellular carcinoma cells in vitro and in an orthotopic xenograft tumour model of HCC
Author(s) -
Herz Corinna,
Hertrampf Anke,
Zimmermann Stefan,
Stetter Nadine,
Wagner Meike,
Kleinhans Claudia,
Erlacher Miriam,
Schüler Julia,
Platz Stefanie,
Rohn Sascha,
MerschSundermann Volker,
Lamy Evelyn
Publication year - 2014
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12412
Subject(s) - telomerase , cancer research , in vivo , apoptosis , cancer cell , telomerase reverse transcriptase , cytotoxicity , cancer , biology , in vitro , chemistry , microbiology and biotechnology , biochemistry , genetics , gene
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 TP 53 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 TMP yP4 further sensitized cancer cells to MTBITC ‐mediated cytotoxicity. Overexpression of h TERT , but not enzyme activity deficient DN h TERT , protected against apoptosis; neither DNA damage nor cytostasis induction by MTBITC was prevented by h TERT 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.