Combination chemotherapy with telomerase inhibitors and genotoxic compounds against breast and colorectal cancers

Telomerase is the specialized reverse transcriptase responsible for the de novo synthesis of telomeric repeats at chromosome ends. Telomerase plays important roles in tumor development and is responsible for the indefinite growth phenotype in cancer. Telomerase over-expression is found in more than 85% of human tumors surveyed. In contrast, normal somatic cells have low or undetectable telomerase expression, making the enzyme an appealing target for the development of anticancer therapy. However, there is a significant time lag between the start of telomerase inhibition therapy and growth inhibition effects, restricting the use of telomerase inhibitors in clinical applications. In addition to telomere maintenance, telomerase participates in cellular recovery processes following genotoxic insults. Genetic suppression of the human telomerase catalytic subunit, telomerase reverse transcriptase (hTERT), diminishes cellular DNA repair capability following double-stranded DNA damage induction, suggesting that the enzyme is involved in the regulation of DNA repair response. I hypothesize that transient telomerase inhibition at the time of genotoxic stimulus will increase cytotoxicity in tumor cells. My studies showed that short-term telomerase inhibition potentiates the cytotoxic effects of DNA damage inducing agents in MCF-7 breast cancer and HT29 colorectal cancer cells, in a cell-cycle dependent and DNA damage mechanism-specific manner. Additionally, I found that the Ataxia Telangiectasia Mutated kinase may interact with telomerase dependent DNA damage repair pathways to further augment cancer cell death. This study provides new mechanistic insight into the roles of telomerase function in cancer cell survival and impetus to design new telomerase-based clinical therapies against breast and colorectal cancers.Pharmaceutical Sciences, Faculty ofGraduat