Effect of penclomedine (NSC-338720) on telomere fusions, chromatin blebbing, and cell viability with and without telomerase activity and abrogated p53 function

Telomeres, or chromosome ends, are essential in maintaining chromosomal integrity. Telomeres consist of a short hexameric sequence, 3′-TTAGGG-5′, repeated in tandem arrays added to chromosomes by the ribonucleoprotein enzyme telomerase. In this study, we assessed whether penclomedine, a novel synthetic pyridine compound presently being evaluated in clinical trials for its anticancer activity, influences telomere fusions (chromosome end-to-end associations) and telomerase activity in cells in culture. We found that penclomedine reduced the mitotic index, induced chromosome end associations in all phases of the cell cycle, and rapidly induced chromatin blebbing in a concentration-dependent manner in both cervical carcinoma (HeLa) cells and in normal human fibroblasts (AG1522). However, the effectiveness of the drug was much more pronounced in HeLa cells. In addition, there was a drug-mediated, concentration-dependent decline in telomerase activity noted in the HeLa cells that correlated with a decrease in mitotic index and an increase in telomere fusions. Interestingly, when the mitotic index, chromatin blebbing, and telomere fusions were compared between the telomerase positive (HeLa) and negative (AG1522) cell types, penclomedine affected chromatin stability to a greater extent in those cells with detectable telomerase activity. In addition, telomerase positive colorectal carcinoma cells with abrogated p53 (RC-10.3 cells) were more sensitive to penclomedine than were telomerase positive cells with wild-type p53 (RKO cells). These studies suggest that penclomedine may have a therapeutic advantage in killing tumor cells that are positive for telomerase activity and defective in p53 function.