Use of Telemorace Inhibition in Combination with Anti-Cancer Drugs to Induce Cell Death in Tumor Cells

摘要

Telomerase is a ribonucleoprotein complex that maintains the stability of chromosome ends the telomeres and regulates cell replicative potential. The enzyme minimally contains a catalytic subunit with reverse transcriptase activity (hTERT) and a RNA subunit (hTR) with a region complementary to the telomeric repeats that is used as template. Telomerase is up-regulated in 05% of breast carcinoma but not in adjacent normal tissues and its activity increases with tumor aggressiveness. Therefore targeting telomerase may represent a promising approach for cancer therapy. Inhibition of telomerase would result in telomere shortening and cell death due to dysfunctional telomeres. The major limitation of this approach is the time necessary for the telomeres to shorten sufficiently to engage cell death. One possibility to overcome this lag phase is to target the telomeres by introducing hTRs with mutations in the template region which results in decreased cell viability and increased apoptosis. The aim of this study is to investigate the feasibility of a new anti-cancer approach based on the combination of telomere disturbances induced by mutant hTR and chemotherapeutic drugs. Our results show that interfering with telomere maintenance in breast cancer cells results in increased susceptibility to anti-cancer drugs independently of initial telomere length and mechanisms of telomere maintenance. These results suggest that this strategy could lead to the development of a general approach for the treatment of all human cancers.