Mechanism of Action of Novel Antiproliferative Oligonucleotides

Abstract

Abstract : G-rich oligonucleotides (GROs) are a novel class of non-antisense nucleic acids that exhibit potent antiproliferative effects against malignant cells, including prostate cancer cells. The antiproliferative activity of GROs was found to correlate with their ability to bind to nucleolin protein. Therefore, it was our hypothesis that these potentially therapeutic agents work by binding to and inhibiting the function of nucleolin. Because nucleolin is a multi functional protein that is involved in many cellular processes including ribosome biogenesis, DNA replication, cell cycle regulation, and apoptosis, the overall goal of this study was to identify the functions of nucleolin that are affected by GRO binding. After the first year of this study, several significant results have emerged. We have shown that GROs cause cell cycle arrest and induce apoptosis in prostate cancer cells but not normal skin cells, and that this arrest is due to specific inhibition of DNA replication. We have further shown that the inhibition of DNA replication may be linked to the ability of GROs to block unwinding by cellular helicases. In addition, we have identified the regions of nucleolin that interact with GROs. These results have been published in peer-reviewed journals and presented at International meetings.