Killing Cancer Cells Through the Biological Clock

Targeted therapy found to shrink tumor growth.

A targeted therapy that takes advantage of a cell’s biological clock was found to kill cancer cells and shrink tumor growth in a recent study.

The study, which appeared in a recent issue of the journal Cancer Discovery, evaluates how targeted DNA structures with a small molecule called 6-thio-2'-deoxyguanosine can halt the growth of cancer cells in culture and decrease the growth of tumors in mice.

"We observed broad efficacy against a range of cancer cell lines with very low concentrations of 6-thiodG, as well as tumor burden shrinkage in mice," senior co-author Jerry W. Shay, MD, said in a press release.

6-thiodG targets a unique mechanism believed to regulate the length of cell life. The aging clock is defined by DNA structures called telomeres, which cap the ends of cell chromosomes to shield them from taking damage, becoming shorter each time the cell divides.

When telomeres are reduced to a critical length, the cell is unable to divide any further before dying through apoptosis.

Cancer cells, however, are protected from apoptosis through the RNA protein complex known as telomerase, which prevents telomeres from shortening with each division of the cell. As a result, extensive research has been previously performed on telomerase as a target for cancer treatment.

Drugs to block the action have been developed, but they have to be administered for long durations to successfully initiate apoptosis and tumor shrinkage, which subsequently carries considerable toxicities. This is partially due to tumor cells carrying chromosomes with different telomere lengths that must be critically shortened to initiate apoptosis.

The use of 6-thiodG as a substrate by telomerase disrupts the typical process in which cells maintain the length of the telomere. As 6-thiodG is not normally used in telomeres, it triggers an alarm the cell recognizes as damage, which stops division and leads to cell death.

Additionally, there were no serious side effects found in the blood, liver, and kidneys of the mice 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," Dr. Shay said. "We believe this small molecule will address an unmet cancer need in an underexplored area that will be rapidly applicable to the clinic."