Telomeres and telomerases as drug targets.
Recent advances in telomerase inhibition have been achieved by using antisense oligonucleotides and ribozymes to target the telomerase mRNA or the telomerase RNA template. Also, small molecules are potent catalytic inhibitors of telomerase. However, therapeutic regimes incorporating these agents will be challenging to implement in the clinic because of their delayed effectiveness. Drugs that directly bind to the telomeres and stabilize secondary DNA structures such as G-quadruplexes are also potent inhibitors of telomerase and disrupt telomere structure. These G-quadruplex-interactive drugs could feasibly be used in synergy with more conventional cytotoxic agents to bring about more immediate responses in cancer cells that are less dependent upon telomere length. Recently, an emerging possible novel use of G-quadruplex-interactive drugs employs their ability to target G-quadruplexes in promoter regions of genes (such as c-MYC), which then serves to repress the production of the human telomerase reverse transcriptase protein.
Rezler
Evonne M
EM
College of Pharmacy, The University of Arizona, 1703 East Mabel, Tucson, Arizona 85721, USA.
Bearss
David J
DJ
Hurley
Laurence H
LH
D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000378:metabolism
D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D019098:Telomerase