Published online Dec 9, 2014. doi: 10.5497/wjp.v3.i4.86
Revised: October 1, 2014
Accepted: October 28, 2014
Published online: December 9, 2014
Telomeres are non-coding tandem repeats of 1000-2000 TTAGGG nucleotide DNA sequences on the 3’ termini of human chromosomes where they serve as protective “caps” from degradation and loss of genes. The “cap” at the end of chromosome required to protect its integrity is a 150-200 nucleotide-long single stranded G-rich 3’ overhang that forms two higher order structures, a T-loop with Sheltering complex, or a G-quadruplex complex. Telomerase is a human ribonucleoprotein reverse transcriptase that continually added single stranded TTAGGG DNA sequences onto the single strand 3’ of telomere in the 5’ to 3’ direction. Telomerase activity is detected in male germ line cells, proliferative cells of renewal tissues, some adult pluripotent stem cells, embryonic cells, but in most somatic cells is not detected. Re-expression or up-regulation of telomerase in tumours cells is considered as a critical step in cell tumorigenesis and telomerase is widely considered as a tumour marker and a target for anticancer drugs. Different approaches have been used in anticancer therapeutics targeting telomerase. Telomerase inhibitors can block directly Human TElomerase Reverse Transcriptase (hTERT) or Human TElomerase RNA telomerase subunits activity, or G-quadruplex and Sheltering complex components, shortening telomeres and inhibiting cell proliferation. Telomerase can become an immune target and GV1001, Vx-001, I540 are the most widespread vaccines used with encouraging results. Another method is to use hTERT promoter to drive suicide gene expression or to control a lytic virus replication. Recently telomerase activity was used to activate pro-drugs such as Acycloguanosyl 5’-thymidyltriphosphate, a synthetic ACV-derived molecule when it is activated by telomerase it does not require any virus or host active immune response to induce suicide gene therapy. Advantage of all these therapies is that target only neoplastic cells without any effects in normal cells, avoiding toxicity and adverse effects of the current chemotherapy. However, as not all the approaches are equally efficient, further studies will be necessary.
Core tip: One of the hallmark of cancer is the replicative immortality of tumor cells guaranteed by telomerase activity that counteracts progressive telomere shortening during cellular replication: this makes telomerase a tumor marker and a target for anticancer drugs. In this review we summarize and update the most recent innovative studies and results on the different strategies that consider telomerase as a target for cancer therapy. In particular, we try to point out the advantages and the potentialities of some innovative approaches, compared to other, equally promising, but that need further investigations.