Natural product based inhibitors of the thioredoxin–thioredoxin reductase system

Wipf, Peter; Lynch, Stephen M.; Birmingham, Anne; Tamayo, Giselle; Jiménez, Allan; Campos, Narciso; Powis, Garth

doi:10.1039/b402431a

Cited by 58 publications

(36 citation statements)

References 26 publications

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“…Several antitumor agents have been shown to be inhibitors of the thioredoxin system, including 1,3-bis-(2-chloro-ethyl)-1-nitrosourea, 1-chloro-2,4-dinitrobenzene, cisplatin and analogs, curcumin, cyclophosphamide, and arsenic trioxide (Gromer et al, 1997;Nordberg et al, 1998;Fang et al, 2005;Witte et al, 2005;Lu et al, 2007;Wang et al, 2007). Specific inhibitors of the thioredoxin system have also been developed, including the thioredoxin-1 inhibitors 2-[(1-methylpropyl)dithio]-1H-imidazole (PX-12) and 2,5-bis[(dimethylamino) methyl]cyclopentanone (NSC131233; Wipf et al, 2004) and the TR1 inhibitors 2-(5-hydroxy-4-oxo-4H-spiro[naphthalene-1,2Ј-naphtho [1,8-de][1,3]dioxine]-6Ј-yloxy)-2-oxoethanminium trifluoroacetate (PX916) (Powis et al, 2006) and AW464 (Chew et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Indolequinones Induced Apoptosis in Human Pancreatic Cancer Cells via Inhibition of Thioredoxin Reductase and Activation of Redox Signaling

Yan¹,

Siegel²,

Newsome³

et al. 2011

Mol Pharmacol

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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 concentrationdependent 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.

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Section: Discussionmentioning

confidence: 99%

Antitumor Indolequinones Induced Apoptosis in Human Pancreatic Cancer Cells via Inhibition of Thioredoxin Reductase and Activation of Redox Signaling

Yan¹,

Siegel²,

Newsome³

et al. 2011

Mol Pharmacol

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“…Several antitumor compounds known to generate electrophiles have been shown to be inhibitors of TrxR (Kirkpatrick et al, 1998;Nordberg et al, 1998;Wipf et al, 2004;Bradshaw et al, 2005;Fang et al, 2005;Witte et al, 2005;Lu et al, 2007;Chew et al, 2008). The selenocysteine of thioredoxin reductase has been shown to be very vulnerable to electrophilic attack because of its low pKa and marked reactivity relative to cysteine residues (Arnér and Holmgren, 2006).…”

Section: Discussionmentioning

confidence: 99%

Potent Activity of Indolequinones against Human Pancreatic Cancer: Identification of Thioredoxin Reductase as a Potential Target

Yan¹,

Shieh²,

Reigan³

et al. 2009

Mol Pharmacol

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The indolequinone ES936 {5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione} was previously developed in our lab as an antitumor agent against pancreatic cancer. The objective of this study was to identify indolequinones with improved potency against pancreatic cancer and to define their mechanisms of action. Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and BxPC-3 were used in in vitro assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) and clonogenic assays]; indolequinones displayed potent cytotoxicity against all three cell lines, and two specific classes of indolequinone were particularly potent agents. These indolequinones induced caspase-dependent apoptosis but no redox cycling or oxidative stress in MIA PaCa-2 and BxPC-3 cells. Selected indolequinones were also screened against the NCI-60 cell line panel and were found to be particularly effective against colon, renal, and melanoma cancer cells. A potential target of these indolequinones was identified as thioredoxin reductase. Indolequinones were found to be potent inhibitors of thioredoxin reductase activity both in pancreatic cancer cells and in cellfree systems. The mechanism of action of the indolequinones was shown to involve metabolic reduction, loss of a leaving group to generate a reactive electrophile resulting in alkylation of the selenocysteine residue in the active site of thioredoxin reductase. In vivo efficacy of the indolequinones was also tested in the MIA PaCa-2 pancreatic tumor xenograft in nude mice, and lead indolequinones demonstrated high efficacy and low toxicity. Inhibition of thioredoxin reductase represents a potential novel target in pancreatic cancer and may provide a biomarker of effect of lead indolequinones in this type of cancer.Pancreatic cancer is the fourth leading cause of cancer death in the United States (Jemal et al., 2008), with a 5-year survival rate of Ͻ5%. Current treatment options of radiation therapy, chemotherapy, and surgery have been ineffective at improving the survival rate (Ghaneh et al., 2007). Development of novel targeted therapeutic approaches is desperately needed.We have reported previously the development of an indolequinone, 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]-indole-4,7-dione (ES936, 1), that exhibited potent growth inhibition effects against human pancreatic cancer cell lines (Dehn et al., 2006). The antitumor activity of ES936 was originally attributed to its role as a mechanism-based inhibitor of human NQO1 [NAD(P)H:quinone oxidoreductase 1 (DT-diaphorase; EC 1.6.99.2)] (Winski et al., 2001). NQO1 inhibition by dicumarol, a nonspecific inhibitor, has been shown to be cytotoxic in human pancreatic cancer cells (Cullen et al., 2003;Lewis et al., 2004). However, when a series of indolequinone compounds

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“…We have reported previously that palmarumycin CP1 and some of its analogues are potent inhibitors of thioredoxin reductase-1 (31). However, all prior compounds were very insoluble and could not be given to animals.…”

Section: Discussionmentioning

confidence: 99%

“…1) were synthesized as described previously (31,32). PX-916 was dissolved at 3 mg/mL in 5% ethanol, 10 mmol/L sodium phosphate (pH 4.0) for i.p.…”

Section: Methodsmentioning

confidence: 99%

“…We have identified the naphthoquinone spiroketal fungal metabolite palmarumycin CP1 as a potent inhibitor of thioredoxin reductase-1, but attempts to exploit the activity of palmarumycin CP1 analogues as antitumor agents in vivo were hampered by their insolubility (31). We have recently reported the synthesis of a series of water-soluble palmarumycin CP1 analogue prodrugs (32).…”

Section: Introductionmentioning

confidence: 99%

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Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase

Powis

Wipf

Lynch

et al. 2006

Molecular Cancer Therapeutics

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The cytosolic thioredoxin redox system composed of thioredoxin-1 and the NADPH-dependent thioredoxin reductase-1 reductase is an important regulator of cell growth and survival. Thioredoxin-1 is overexpressed in many human tumors where it is associated with increased cell proliferation, decreased apoptosis, and decreased patient survival. We hypothesized that thioredoxin reductase-1 provides a target to inhibit the activity of overexpressed thioredoxin-1 for the development of novel anticancer agents. We found that the naphthoquinone spiroketal fungal metabolite palmarumycin CP1 is a potent inhibitor of thioredoxin reductase-1, but attempts to exploit the activity of palmarumycin CP1 analogues as antitumor agents in vivo were hampered by their insolubility. We have therefore developed PX-916, a water-soluble prodrug of a palmarumycin CP1 analogue. PX-916 rapidly releases the parent compound at physiologic pH and in plasma but is stable at acid pH, allowing its i.v. administration. PX-916 is a potent inhibitor of purified human thioredoxin reductase-1 and of thioredoxin reductase-1 activity in cells and tumor xenografts when given to mice and inhibits the downstream targets of thioredoxin-1 signaling, hypoxiainducible factor-1A, and vascular endothelial growth factor in tumors. PX-916 showed excellent antitumor activity against several animal tumor models with some cures. Thus, the study shows that water-soluble inhibitors of thioredoxin reductase-1, such as PX-916, can block thioredoxin-1 signaling in tumors producing marked inhibition of tumor growth. [Mol Cancer Ther 2006; 5(3):630 -6]

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Natural product based inhibitors of the thioredoxin–thioredoxin reductase system

Cited by 58 publications

References 26 publications

Antitumor Indolequinones Induced Apoptosis in Human Pancreatic Cancer Cells via Inhibition of Thioredoxin Reductase and Activation of Redox Signaling

Antitumor Indolequinones Induced Apoptosis in Human Pancreatic Cancer Cells via Inhibition of Thioredoxin Reductase and Activation of Redox Signaling

Potent Activity of Indolequinones against Human Pancreatic Cancer: Identification of Thioredoxin Reductase as a Potential Target

Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase

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