Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death

The correlation between telomerase activity and human tumors has led to the hypothesis that tumor growth requires reactivation of telomerase and that telomerase inhibitors represent a class of chemotherapeutic agents. Herein, we examine the effects of inhibition of telomerase inside human cells. Pep tide nucleic acid and 2'-O-MeRNA oligomers inhibit telomerase, leading to p rogressive telomere shortening and causing immortal human breast epithelial cells to undergo apoptosis with increasing frequency until no cells remain . Telomere shortening is reversible: if inhibitor addition is terminated, t elomeres regain their initial lengths. Our results validate telomerase as a target for the discovery of anticancer drugs and supply general insights i nto the properties that successful agents will require regardless of chemic al type. Chemically similar oligonucleotides are in clinical trials and hav e well characterized pharmacokinetics, making the inhibitors we describe pr actical lead compounds for testing for an antitelomerase chemotherapeutic s trategy.