DNA G-quadruplexes, telomere-specific proteins and telomere-associated enzymes as potential targets for new anticancer drugs

Telomeres and telomerase have been subjects to a tremendous attention from scientists and oncologists during the past 5 years. This interest has been motivated by the potential of telomerase as a tumor marker for the diagnosi s and the prognosis of cancer. The possible use of telomerase or telomeres as new targets for anticancer drugs also triggered investigations. The expr ession of telomerase was found in overall 85% of cancers. Telomerase is ear ly expressed during oncogenesis with a gradient indicating that a high leve l of telomerase expression could be associated with a bad prognosis. Theref ore, drugs targeting telomerase and telorneres might be useful in many huma n tumors with little restrictions regarding the tumor type or on the stage of the disease. Moreover, since telomerase is not or slightly expressed in normal cells, it has been postulated that drugs targeting telomerase would induce low toxicity. The race for the discovery of telomerase inhibitors has started while the i dentification of the components controlling telomerase, telomeres, cell sur vival, senescence, and apoptosis was still in progress. The recent identifi cation of components regulating telomere length and telomerase expression ( TRF1, TRF2, and tankyrase) opened a variety of new opportunities to control telomerase/telomere interactions. Meanwhile, a proof of principle was prov ided that changing telomere interactions with telomere binding proteins by chemical or biological means can induce cancer cell death. Interestingly, r ecent data challenge the old paradigm which suggested that a long exposure to telomerase and telomere inhibitors is necessary to induce anticancer eff ects. In this paper, we review the most recent information concerning the regulat ion of telomere length and telomerase expression, with emphasis on mechanis ms that might translate into new drug discovery.