ABSTRACT
Certain G-quadruplex forming guanine-rich oligonucleotides (GROs), including AS1411, are endowed with cancer-selective antiproliferative activity. They are known to bind to nucleolin protein, resulting in the inhibition of nucleolin-mediated phenomena. However, multiple nucleolin-independent biological effects of GROs have also been reported, allowing them to be considered promising candidates for multi-targeted cancer therapy. Herein, with the aim of optimizing AS1411 structural features to find GROs with improved anticancer properties, we have studied a small library of AS1411 derivatives differing in the sequence length and base composition. The AS1411 derivatives were characterized by using circular dichroism and nuclear magnetic resonance spectroscopies and then investigated for their enzymatic resistance in serum and nuclear extract, as well as for their ability to bind nucleolin, inhibit topoisomerase I, and affect the viability of MCF-7 human breast adenocarcinoma cells. All derivatives showed higher thermal stability and inhibitory effect against topoisomerase I than AS1411. In addition, most of them showed an improved antiproliferative activity on MCF-7 cells compared to AS1411 despite a weaker binding to nucleolin. Our results support the hypothesis that the antiproliferative properties of GROs are due to multi-targeted effects.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aptamers, Nucleotide/chemistry , Nucleic Acid Heteroduplexes/chemistry , Oligodeoxyribonucleotides/chemistry , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Aptamers, Nucleotide/pharmacology , Circular Dichroism , DNA Topoisomerases, Type I/metabolism , Deoxyribonucleases/metabolism , Drug Screening Assays, Antitumor/methods , Drug Stability , Female , Fluorescence Resonance Energy Transfer , Humans , MCF-7 Cells , Magnetic Resonance Spectroscopy , Oligodeoxyribonucleotides/pharmacology , Phosphoproteins/metabolism , RNA-Binding Proteins/metabolism , Surface Plasmon Resonance , Thymine/chemistry , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/pharmacology , NucleolinABSTRACT
BACKGROUND: Viral infections are among the most common problems in health-care practice. Natural products offer great promise as potentially effective antiviral drugs. Propolis is a honeybee product with biological properties and therapeutic applications. We aimed to investigate the antiviral activity of different extracts of Standardized Propolis Preparations (M.E.D.®) with glycol, ethanol, glycerol and soya oil, against herpes simplex type-1 (HSV-1) and type 2 (HSV-2) viruses. METHODS: Chemical composition and antiviral activity of each extract were determined. The selective index (SI=CC50/EC50) was determined as a parameter to indicate the in vitro antiviral activity of the extracts compared with acyclovir as the control. RESULTS: SI values of glycol, ethanol, glycerol, soya oil extracts and acyclovir were determined as 6.8, 4.1, 2.2, 3.3 and 6.3 against HSV-1, and as 6.4, 7.7, 1.9, 4.2 and 2.9 against HSV-2, respectively. Glycolic propolis extract was found to possess a greater antiviral activity than acyclovir for both HSV-1 and 2, while glycolic, ethanolic and soya oil preparations were found to have more significant activity than acyclovir for HSV-2. CONCLUSIONS: It was determined that standardized propolis preparations have antiviral bioactivity against HSV.
Subject(s)
Herpesvirus 1, Human , Propolis , Acyclovir/pharmacology , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Ethanol/pharmacology , Glycerol/pharmacology , Glycols/pharmacology , Herpesvirus 2, Human , Humans , Plant Extracts/pharmacology , Propolis/chemistry , Propolis/pharmacology , Soybean Oil/pharmacologyABSTRACT
G-quadruplex (G4) and i-motif (iM) are four-stranded non-canonical nucleic acid structural arrangements. Recent evidences suggest that these DNA structures exist in living cells and could be involved in several cancer-related processes, thus representing an attractive target for anticancer drug discovery. Efforts toward the development of G4 targeting compounds have led to a number of effective bioactive ligands. Herein, employing several biophysical methodologies, we studied the ability of some well-known G4 ligands to interact with iM-forming DNA. The data showed that the investigated compounds are actually able to interact with both DNA in vitro, thus acting de facto as multi-target-directed agents. Interestingly, while all the compounds stabilize the G4, some of them significantly reduce the stability of the iM. The present study highlights the importance, when studying G4-targeting compounds, of evaluating also their behavior toward the i-motif counterpart.
