Research carried out at the University of Texas Southwestern Medical Center (TX, USA) has succeeded in targeting telomeres with a small molecule termed 6-thio-2′-deoxyguanosine (6-thiodG), which takes advantage of the cell’s ‘biological clock’ to kill cancer cells and shrink tumor growth. The study was recently published in Cancer Discovery.
The research team demonstrated that 6-thiodG could stop the growth of a range of cancer cells in culture and decrease the growth of tumors in mice. This small molecule acts by targeting a unique mechanism that is thought to regulate the longevity of a cell, otherwise described as an aging clock.
This aging process is defined by telomeres, which cap the ends of the cell’s chromosomes to protect them from damage and progressively shorten with each round of DNA replication. Once telomeres have shortened to a critical length, the cell can no longer divide and dies via apoptosis.
Cancer cells are protected from apoptosis by telomerase, which ensures that telomeres do not shorten with every division. Telomerase has therefore been the subject of intense research as a target for cancer therapy. Drugs that successfully block its action have been developed, however these drugs need to be administered for long periods of time to successfully trigger cell death and shrink tumors, leading to considerable toxicities. This outcome is partially due to cells in any one tumor having chromosomes with different telomere lengths and any one cell’s telomeres must be critically shortened to promote cell death.
6-thiodG is preferentially used as a substrate by telomerase and disrupts the normal way cells maintain telomere length. As 6-thiodG is not normally used in telomeres, the presence of the compound is recognized as DNA damage, resulting in cell cycle arrest and apoptosis.
Telomerase is an almost universal oncology target, yet there are few telomerase-directed therapies in human clinical trials. Importantly, unlike many other telomerase-inhibiting compounds, the researchers did not observe serious side effects in the blood, liver or kidneys of the mice that were treated with 6-thiodG.
“Since telomerase is expressed in almost all human cancers, this work represents a potentially innovative approach to targeting telomerase-expressing cancer cells with minimal side effects on normal cells,” commented Jerry Shay from Southwestern Medical Center. “We believe this small molecule will address an unmet cancer need in an underexplored area that will be rapidly applicable to the clinic.”
Sources: Mender I, Gryaznov S, Dikmen Z G, Wright W E, Shay J W. Induction of Telomere Dysfunction Mediated by the Telomerase Substrate Precursor 6-Thio-2′-Deoxyguanosine. Cancer Discovery doi: 10.1158/2159-8290.CD-14-0609 (2014) [Epub ahead of print]; UT Southwestern Medical Center press release