Telomeres with a small molecule called 6-thio-2'-deoxyguanosine (6-thiodG) that takes advantage of the cell's 'biological clock' to kill cancer cells and shrink tumor growth have been targeted by cell biologists at University of Texas (UT) Southwestern Medical Center. Mice studies revealed that 6-thio-2'-deoxyguanosine could stop the growth of cancer cells in culture and decrease the growth of tumors.
6-thiodG acts by targeting a unique mechanism that regulates how long cells can stay alive, a type of biological clock. This aging clock is defined by DNA structures known as telomeres, which cap the ends of the cell's chromosomes to protect them from damage, and which become shorter every time the cell divides. Once telomeres shorten to a critical length, they can no longer divide and die though a process known as apoptosis.
Cancer cells are protected from this death by RNA protein complex called telomerase, which ensures that telomeres do not shorten with every cell division. 6-thiodG is preferentially used as a substrate by telomerase and disrupts the normal process in which cells maintain telomere length. As 6-thiodG is not normally used in telomeres, the presence of the compound acts as an 'alarm signal' that is recognized by the cell as damage, due to which the cell stops dividing and dies.
Telomerase is an universal oncology target. However, there are few telomerase-directed therapies in human clinical trials. Senior author Dr. Woodring E. Wright said, "Using telomerase to incorporate toxic products into telomeres is remarkably encouraging at this point."
Unlike many other telomerase-inhibiting compounds, the researchers did not observe serious side effects in the blood, liver and kidneys of the mice that were treated with 6-thiodG. Senior author Dr. Jerry W. Shay said, "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. We believe this small molecule will address an unmet cancer need in an under explored area that will be rapidly applicable to the clinic."
The study is published in the journal 'Cancer Discovery'.