Accession Number : ADA473655


Title :   Mechanistic Studies of Oligonucleotide Aptamers With Potent Antiproliferative and Pro-Apoptotic Activity Against Prostate Cancer Cells


Descriptive Note : Final rept. 1 May 2004-30 Apr 2007


Corporate Author : LOUISVILLE UNIV KY


Personal Author(s) : Bates, Paul J


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a473655.pdf


Report Date : May 2007


Pagination or Media Count : 87


Abstract : G-rich oligos (GROs) are a novel class of protein-binding aptamers that selectively inhibit the proliferation of cancer cells. One of the GROs, named AS1411 (formerly AGRO100), is currently in human clinical trials for the treatment of advanced cancers. The GROs specifically target nucleolin, a multifunctional protein that is present at high levels in prostate cancer cells, but it is not yet fully understood how binding of GROs to nucleolin inhibits cancer cell proliferation. The purpose of the project was to explore the mechanism of the AS1411 anticancer effects. The specific hypothesis being tested was that AS1411 binds to nucleolin and modulates its protein-protein interactions, leading to alterations in nucleolin function and pleiotropic biological effects. The results of this study support the validity of that hypothesis. Numerous proteins that bind to nucleolin and/or AS1411 were identified and many were found to be altered in prostate cancer cells treated with AS1411. Several novel activities of AS1411 and previously unknown complexes of nucleolin were identified. For example, AS1411 blocked NF-kappaB signaling by affecting a nucleolin complex containing NEMO/IKKgamma, and upregulation of tumor suppressor geneST7 was linked to redistribution of a PRMT5-nucleolin complex. These new data indicate AS1411 affects the trafficking of a subset of nucleolin complexes.


Descriptors :   *CELLS(BIOLOGY) , *OLIGOMERS , *PROSTATE CANCER , *APOPTOSIS , *NUCLEOTIDES , HUMANS , INTERACTIONS , MOLECULES , PROTEINS , POTENCY , CLINICAL TRIALS , GROWTH(PHYSIOLOGY) , CHEMOTHERAPY , PHARMACOLOGY , MULTIPURPOSE , HYPOTHESES , RESPONSE(BIOLOGY) , LINKAGES


Subject Categories : Biochemistry
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE