Abstract |
Indolequinones (IQs) were developed as potential antitumor agents against human pancreatic cancer. IQs exhibited potent antitumor activity against the human pancreatic cancer cell line MIA PaCa-2 with growth inhibitory IC(50) values in the low nanomolar range. IQs were found to induce time- and concentration-dependent apoptosis and to be potent inhibitors of thioredoxin reductase 1 (TR1) in MIA PaCa-2 cells at concentrations equivalent to those inducing growth-inhibitory effects. The mechanism of inhibition of TR1 by the IQs was studied in detail in cell-free systems using purified enzyme. The C-terminal selenocysteine of TR1 was characterized as the primary adduction site of the IQ-derived reactive iminium using liquid chromatography-tandem mass spectrometry analysis. Inhibition of TR1 by IQs in MIA PaCa-2 cells resulted in a shift of thioredoxin-1 redox state to the oxidized form and activation of the p38/c-Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathway. Oxidized thioredoxin is known to activate apoptosis signal-regulating kinase 1, an upstream activator of p38/JNK in the MAPK signaling cascade and this was confirmed in our study providing a potential mechanism for IQ-induced apoptosis. These data describe the redox and signaling events involved in the mechanism of growth inhibition induced by novel inhibitors of TR1 in human pancreatic cancer cells.
|
Authors | Chao Yan, David Siegel, Jeffery Newsome, Aurelie Chilloux, Christopher J Moody, David Ross |
Journal | Molecular pharmacology
(Mol Pharmacol)
Vol. 81
Issue 3
Pg. 401-10
(Mar 2012)
ISSN: 1521-0111 [Electronic] United States |
PMID | 22147753
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
|
Chemical References |
- Antineoplastic Agents
- Indolequinones
- Thioredoxin-Disulfide Reductase
|
Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Cell Line, Tumor
- Chromatography, Liquid
- Humans
- Indolequinones
(pharmacology)
- Oxidation-Reduction
- Pancreatic Neoplasms
(enzymology, metabolism, pathology)
- Signal Transduction
(drug effects)
- Tandem Mass Spectrometry
- Thioredoxin-Disulfide Reductase
(antagonists & inhibitors)
|