Targeting human telomerase in cancer therapy.
Telomerase is a specialized RNA template-containing reverse transcriptase that mediates telomere repeat synthesis at chromosome ends. The maintenance of telomere length and integrity is essential for cell survival. Telomerase is active in most immortal and tumor cells, whereas the majority of normal human cells demonstrate no detectable activity and undergo telomere shortening. The identification of a possible role for telomerase in cellular aging and cancer has led to numerous studies designed to characterize this ribonucleoprotein enzyme. Inhibiting telomerase activity in immortal human cells reduces cellular proliferative capacity and can lead to cell death. Identifying mechanisms to specifically inhibit telomerase activity in malignant cells could thus be of great therapeutic value in the treatment of cancer. In this review, we summarize the current understanding of the mechanism of action of human telomerase. The biochemical characterization of telomerase is necessary for the design and evaluation of antitelomerase therapies. Different strategies are currently under investigation to design inhibitors that target the reverse transcriptase and RNA components of the telomerase complex. Recent advances in the design of these inhibitors and their properties are discussed.
Huard
Sylvain
S
Department of Anatomy and Cell Biology, McGill University, and Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis Jewish General Hospital, 3755 Côte Ste. Catherine Road, Montréal, Québec, Canada.
Autexier
Chantal
C
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020134:Catalytic Domain / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009841:Oligonucleotides; D019098:Telomerase