Triethylenetetramine Pharmacology and Its Clinical Applications

Abstract

Triethylenetetramine (TETA), a Cu II -selective chelator, is commonly used for the treatment of Wilson's disease. Recently, it has been shown that TETA can be used in the treatment of cancer because it possesses telomerase inhibiting and anti-angiogenesis properties. Although TETA has been used in the treatment of Wilson's disease for decades, a comprehensive review on TETA pharmacology does not exist. TETA is poorly absorbed with a bioavailability of 8 to 30%. It is widely distributed in tissues with relatively high concentrations measured in liver, heart, and kidney. It is mainly metabolized via acetylation, and two major acetylated metabolites exist in human serum and urine. It is mainly excreted in urine as the unchanged parent drug and two acetylated metabolites. It has a relatively short half-life (2 to 4 hours) in humans. The most recent discoveries in TETA pharmacology show that the major pharmacokinetic parameters are not associated with the acetylation phenotype of N-acetyltransferase 2, the traditionally regarded drug acetylation enzyme, and the TETA-metabolizing enzyme is actually spermidine/spermine acetyltransferase. This review also covers the current preclinical and clinical application of TETA. A much needed overview and up-to-date information on TETA pharmacology is provided for clinicians or cancer researchers who intend to embark on cancer clinical trials using TETA or its close structural analogs. Mol Cancer Ther; 9(9); 2458-67. ©2010 AACR.

Complex N-Acetylation of Triethylenetetramine

“…Copper and/or iron chelation affects the regulation and the functions of hypoxia-inducible factor 1␣, and its potential interaction with SSAT1/2 renders TETA action very complicated (Baek et al, 2007a,b;Feng et al, 2009). In light of the previous and present findings, it is clear that additional studies with TETA and SpmTrien in animal models of type 2 diabetes and cancer models are warranted (Yu et al, 2006;Gupte and Mumper, 2009;Lu et al, 2010Lu et al, , 2010a.…”

“…N 1 AcTETA and N 1 N 8 DiAcTETA are characterized as the major metabolites of TETA in humans (Lu et al, 2010b), but the N-acetylase(s) responsible for TETA metabolism has remained uncharacterized (Lu, 2010). In this study, we demonstrated that SSAT1 acetylated TETA in vivo, because SSAT1-overexpressing mice metabolized TETA at an accelerated rate compared with syngenic mice.…”

“…TETA has proven to be a very interesting drug molecule having potential in the treatment of several diseases (Lu, 2010). N 1 AcTETA and N 1 N 8 DiAcTETA are characterized as the major metabolites of TETA in humans (Lu et al, 2010b), but the N-acetylase(s) responsible for TETA metabolism has remained uncharacterized (Lu, 2010).…”

Metabolomic analysis of rat serum in streptozotocin-induced diabetes and after treatment with oral triethylenetetramine (TETA)

“…Some of the already known mechanisms of action and effects of TETA (for a review, see [42]) include: (i) increased urinary copper excretion, (ii) decreased intestinal copper absorption, (iii) telomerase inhibition, (iv) suppression of angiogenic mediators (that is, vascular endothelial growth factor-1, fibroblast growth factor-1, IL-1, IL-6, IL-8 and NFκB), (v) activation of the p38 mitogen-activated protein kinase pathway, (vi) reduced over-expression of Cu/Zn superoxide dismutase, (vii) reversed activation of transforming growth factor-beta and fibrosis in diabetes-induced nephropathy, and (viii) suppressed carbonyl stress in lenses of diabetic rats. However, TETA is likely to have additional mechanisms of action and the objective was to identify other TETA-related changes in the diabetic rats by applying metabolomic technologies.…”

Overcoming Platinum Resistance through the Use of a Copper-Lowering Agent

“…Recent discoveries revealed that hCtr1 regulates intracellular copper homeostasis, which, in turn, controls hCtr1 expression via a homeostatic feedback loop (4). Copper-lowering agents increased the expression of hCtr1, subsequently resensitizing tumor cells to platinum therapy (5). Here, we report preliminary evidence that a copper-lowering agent may be able to, at least partially, reverse platinum resistance in patients with platinum-resistant high-grade epithelial ovarian cancer.…”