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DOI: 10.1055/s-0034-1394532
Relevance of telomerase inhibition by 4-methylthiobutyl isothiocyanate in tumor cells of the liver
The Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer in the world.[1] Due to its aggressive nature, the low response rate to chemotherapeutic agents and its high recurrence rate, prognosis for patients diagnosed with HCC is bad.[2] In contrast to cancer cells, normal human cells have no or low telomerase levels which makes it an attractive target for anti-cancer drugs. Isothiocyanates, naturally compounds from plants of the family Brassicaceae are known for their chemopreventive and -therapeutic actions both in vitro and in vivo. [3,4,5] However, the mechanisms of these pleiotrophic agents against cancer cells are still subject of intense research. Here we investigated the relevance of telomerase abrogation for the efficacy of 4-methylthiobutyl isothiocyanate (MTBITC, erucin) against HCC in vitro and in vivo. MTBITC effectively inhibited telomerase, independent from TP53 as demonstrated in HCC cell lines (wt-TP53, mut-TP53, del-TP53) and chemoresistant subpopulations. This was analyzed by the telomeric repeat amplification protocol (TRAP assay) and confirmed on protein and mRNA level. Moreover, we showed that MTBITC-treatment significantly blocked telomerase activity in an orthotopic human liver cancer xenograft model without affecting enzyme activity of adjacent normal tissue. Telomerasae interference played indeed an essential step in the chemotherapeutic efficacy of MTBITC as demonstrated by using a selective chemical inhibitor of telomerase or hTERT overexpressing cells In conclusion, this is the first study for isothiocyanate drugs to demonstrate systematically telomerase suppression in vitro and in vivo and could be valuable in improving the effectiveness of future therapeutic interventions with these agents against liver cancer.
Keywords: 4-methylthiobutyl isothiocyanate, erucin, hTERT/telomerase suppression, liver cancer, adjuvant chemotherapy
References:
[1] Ferlay, J. et. al. (2010) Int J Cancer; 127:2893 – 2917.
[2] Chan, K.T. et al. (2004) Cancer Chemother Pharmacol 53:519 – 526.
[3] Bianchini F and Vainio H (2004) Drug Metab Rev 36: 655 – 667
[4] Lamy E. et. al. (2013) PLoS One 2013;8(8):e70846.
[5] Lamy E. et. al. (2013) PLoS One. 2013;8(1):e53240.