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.