Novel Two-Pronged Method Targets Cancer Cells’ Telomerase and Chromosomes

An international team of researchers has developed a new technique for identifying potential cancer drugs that could streamline the development of therapies. The team devised a way to screen potential drug compounds to select those that interfere with tumor cells in two ways.

Their study (“Systematic Analysis of Compounds Specifically Targeting Telomeres and Telomerase for Clinical Implications in Cancer Therapy”), published in Cancer Research, seeks to build on an existing method of finding drugs that target telomerase. Scientists hope to identify drugs that not only inhibit this protein but also induce errors when cancer cells divide their chromosomes to form new cells.

An attack on two fronts could prevent cancerous cells from growing and, therefore, kill tumors, say the researchers.

“The targeting of telomerase and telomere maintenance mechanisms represents a promising therapeutic approach for various types of cancer. In this work, we designed a new protocol to screen for and rank the efficacy of compounds specifically targeting telomeres and telomerase. This approach used two isogenic cell lines containing a circular human artificial chromosome (HAC, lacking telomeres) and a linear HAC (containing telomeres) marked with the EGFP transgene; compounds that target telomerase or telomeres should preferentially induce loss of the linear HAC but not the circular HAC,” wrote the investigators.

“Our assay allowed quantification of chromosome loss by routine flow cytometry. We applied this dual-HAC assay to rank a set of known and newly developed compounds, including G-quadruplex (G4) ligands. Among the latter group, two compounds, Cu-ttpy and Pt-ttpy, induced a high rate of linear HAC loss with no significant effect on the mitotic stability of a circular HAC. Analysis of the mitotic phenotypes induced by these drugs revealed an elevated rate of chromatin bridges in late mitosis and cytokinesis as well as UFB (ultrafine bridges). Chromosome loss after Pt-ttpy or Cu-ttpy treatment correlated with the induction of telomere-associated DNA damage. Overall, this platform enables identification and ranking of compounds that greatly increase chromosome mis-segregation rates as a result of telomere dysfunction and may expedite the development of new therapeutic strategies for cancer treatment.”

Researchers at the University of Edinburgh, the Institute Curie in Paris, the U.S. National Cancer Institute, and the Kazusa DNA Institute of Japan tested drug compounds using artificial human chromosomes with in-built fluorescent markers. This allowed the team to detect when and how often drug treatment caused the loss of chromosomes.

Drugs identified in this way were then tested in different types of cancer cells to investigate exactly how they were able to disrupt chromosome division at a high rate. Researchers hope these newly identified drugs can inform the development of more effective therapies.

“Our approach enables the selection of drug compounds that disrupt normal division of cancer cells,” said William C Earnshaw, Ph.D., professor of chromosome dynamics at the University of Edinburgh’s School of Biological Sciences, who participated in the study. “Our hope is that this can result in the development of more effective therapies to target tumors.”

“We hope our two-pronged approach can prove useful in targeting a range of cancers using newly selected, more efficient drugs,” added Mar Carmena, Ph.D., senior research associate at the University of Edinburgh’s School of Biological Sciences, who also took part in the study.