Pharmacodynamics of Telomerase Inhibition and Telomere Shortening by Noncytotoxic Suramin
Journal Title: The AAPS Journal - Year 2015, Vol 17, Issue 1
Abstract
We reported that suramin is an effective chemosensitizer at noncytotoxic concentrations (<50 μM); this effect was observed in multiple types of human xenograft tumors in vitro and in vivo. Clinical evaluation of noncytotoxic suramin is ongoing. Because (a) suramin inhibits reverse transcriptase, (b) telomerase is a reverse transcriptase, and (c) inhibition of telomerase enhances tumor chemosensitivity, we studied the pharmacodynamics of noncytotoxic suramin on telomerase activity and telomere length in cultured cells and tumors grown in animals. In three human cancer cells that depend on telomerase for telomere maintenance (pharynx FaDu, prostate PC3, breast MCF7), suramin inhibited telomerase activity in cell extracts and intact cells at concentrations that exhibited no cytotoxicity (IC50 of telomerase was between 1 and 3 μM vs. >60 μM for cytotoxicity), and continuous treatment at 10–25 μM for 6 weeks resulted in gradual telomere shortening (maximum of 30%) and cell senescence (measured by β-galactosidase activity and elevation of mRNA levels of two senescence markers p16 and p21). In contrast, noncytotoxic suramin did not shorten the telomere in telomerase-independent human osteosarcoma Saos-2 cells. In mice bearing FaDu tumors, treatment with noncytotoxic suramin for 6 weeks resulted in telomere erosion in >95% of the tumor cells with an average telomere shortening of >40%. These results indicate noncytotoxic suramin inhibits telomerase, shortens telomere and induces cell senescence, and suggest telomerase inhibition as a potential mechanism of its chemosensitization.
Authors and Affiliations
Yuebo Gan, Jie Lu, Bertrand Z. Yeung, Christopher T. Cottage, M. Guillaume Wientjes, Jessie L. -S. Au
Keywords
Related Articles
- EP ID EP680912
- DOI 10.1208/s12248-014-9703-7
- Views 55
- Downloads 0
Mixed Effects Modeling Using Stochastic Differential Equations: Illustrated by Pharmacokinetic Data of Nicotinic Acid in Obese Zucker Rats
Inclusion of stochastic differential equations in mixed effects models provides means to quantify and distinguish three sources of variability in data. In addition to the two commonly encountered sources, measurement err...
Comparison of Drug Permeabilities and BCS Classification: Three Lipid-Component PAMPA System Method versus Caco-2 Monolayers
PC18:1 and PS18:1 were purchased from Avanti Polar Lipids (Alabaster, AL). Hydrophobic microfilter plates (polyvinylidene fluoride, 0.45 μm) were purchased from Millipore Corporation (Bedford, MA). Caco-2...
Synthesis and Pharmacological Evaluation of 6-Acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a Cocaine Antagonist, in Rodents
The online version of this article (doi:10.1208/s12248-011-9274-9) contains supplementary material, which is available to authorized users.
Pharmacokinetic and pharmacodynamic effects of high-dose monoclonal antibody therapy in a rat model of immune thrombocytopenia
Intravenous administration of pooled, polyvalent human immunoglobulin (IVIG) has been used for over 20 years as a therapy for immune thrombocytopenia (ITP). IVIG is available in limited quantities, and clinical preparati...
Bilirubin—A Potential Marker of Drug Exposure in Atazanavir-Based Antiretroviral Therapy
The objective of this work was to examine the atazanavir–bilirubin relationship using a population-based approach and to assess the possible application of bilirubin as a readily available marker of atazanavir ex...