Targeting Human Telomerase by Antisense Oligonucleotides and Ribozymes: An Update

Human telomerase is a ribonucleoprotein enzyme complex that, when expressed at high level, enables cells to maintain telomere length, allowing indefinite replicative capacity. The notion that telomerase is reactivated in 80-90% of human cancers has led to the proposal of telomerase as a promising therapeutic target for novel anticancer interventions. In this review an update regarding antisense-based approaches used thus far to inhibit telomerase activity in human cancer cells is provided. All these strategies significantly inhibited the enzyme's catalytic activity in several experimental tumour models. However, while in some studies tumour cell growth arrest was observed as a consequence of telomere shortening after prolonged telomerase inhibition, other studies have shown that antisense-based treatments targeting telomerase induced rapid loss (i.e. within a few days) of tumour cell viability with concomitant apoptosis. These findings have conferred to telomerase a putative pro-survival and anti-apoptotic role, which would be independent from its telomereelongating activity and rely on telomere capping function of the enzyme. However, the role of telomerase in tumourigenesis, beyond the classical mechanism of telomere lengthening, needs to be further investigated to provide a better rationale for the use of antitelomerase-based therapies in clinical trials.