Oligonucleotides and G-quadruplex Stabilizers: Targeting Telomeres and Telomerase in Cancer Therapy

Abstract

Cancer is a leading cause of death worldwide and an estimated 1 in 4 deaths in the United States is due to cancer. Despite recent advances in cancer treatment, adverse effects related to cancer therapy remain a limiting factor for many patients. The ideal cancer treatment would selectively target cancerous cells while sparing normal, healthy cells to offer maximal therapeutic benefit while minimizing toxicity. Telomeres are structurally unique DNA sequences at the end of human chromosomes, which play an integral role in the cellular mortality of normal cells. As telomeres shorten with successive cellular divisions, cells develop chromosomal instability and undergo either apoptosis or senescence. In many cancers, this apoptosis or senescence is avoided as normal telomere length is maintained by a ribonucleoprotein reverse transcriptase called telomerase. Telomerase is expressed in more than 85% of all cancers and confers cancerous cells with a replicative immortality, which is a hallmark of malignant tumors. In contrast, telomerase activity is not detectable in the majority of normal somatic cell populations. Therefore, the targeting of telomerase and telomere maintenance mechanisms represent a potentially promising therapeutic approach for various types of cancer. This review evaluates the roles of GRN163L, T-oligo and small molecule G-quadruplex stabilizers as potential anticancer therapies by targeting telomerase and other telomere maintenance mechanisms.

Selectivity of major isoquinoline alkaloids from Chelidonium majus towards telomeric G-quadruplex: A study using a transition-FRET (t-FRET) assay

“…The guanine-rich, single strand terminal ends of telomeres may fold into a strong and stable intramolecular G4 structures, which prevents accessibility to telomerase [23]. Various strategies have targeted this structure to suppress telomerase activity in rapidly dividing cancer cells [24][25][26].…”

Targeting the Telomere with T-Oligo, G Quadruplex Stabilizers, and Tankyrase Inhibitors

“…The t-loop prevents the single-stranded overhang from being recognized as a double stranded break and protects telomeres from nucleolytic degradation or non-homologous end-joining [4,5]. The formation of the t-loop is facilitated by shelterin, a six-protein complex composed of TRF1, TRF2, TIN2, POT1, TPP1, and Rap1 [6], which has a critical role in telomere length maintenance [2]. All shelterin proteins except POT1 bind to doublestranded regions of the telomere.…”

“…Additionally, the t-loop is partially stabilized by the guanine-rich character of the 3' overhang, which is hypothesized to form G-quadruplexes, which are four-stranded DNA structures stabilized by hydrogen bonds between guanine quartets. Increasing the amount of G-quadruplex regions has been shown to prevent telomerase, the enzyme complex that lengthens telomeres, from binding to the telomere overhang [6].…”

“…Telomerase has recently become an attractive target for cancer therapies because it is inappropriately overexpressed in more than 85% of cancers, while most normal cells have minimal or no detectable activity [9,10]. When telomerase is activated, telomere length is stabilized and DDRs initiated by criticallyshortened telomeres do not occur, thereby allowing cancer cells to proliferate by evading apoptosis or senescence [6].…”

“…However, ALT is still poorly understood, and it is possible that other mechanisms of ALT exist [12]. In addition, it is thought that drug-induced resistance to telomerase inhibitors may occur through the activation of ALT pathways in some cancers [6,13].…”