Motexafin Gadolinium, a Tumor-selective Drug Targeting Thioredoxin Reductase and Ribonucleotide Reductase

Hashemy, Seyed Isaac; Ungerstedt, Johanna; Avval, Farnaz Zahedi; Holmgren, Arne

doi:10.1074/jbc.m511373200

Cited by 149 publications

(92 citation statements)

References 43 publications

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“…A compensatory upregulation of the GSH-dependent system and phase II enzymes on Txnrd1 deletion and the high susceptibility of Txnrd1-deficient tumors toward pharmacologic inhibition of GSH suggest that simultaneous inhibition of more than one antioxidant systems is particularly efficient in killing tumor cells. Indeed, the redox modifiers like phenethyl isothiocyanate (8) and Motexifen gadolinium (49) have been reported to effectively kill tumor cells by causing the preferential accumulation of ROS, oxidative damage in mitochondria, inactivation of redox-sensitive molecules, and massive cell death.…”

Section: Discussionmentioning

confidence: 99%

Loss of Thioredoxin Reductase 1 Renders Tumors Highly Susceptible to Pharmacologic Glutathione Deprivation

et al. 2010

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Tumor cells generate substantial amounts of reactive oxygen species (ROS), engendering the need to maintain high levels of antioxidants such as thioredoxin (Trx)-and glutathione (GSH)-dependent enzymes. Exacerbating oxidative stress by specifically inhibiting these types of ROS-scavenging enzymes has emerged as a promising chemotherapeutic strategy to kill tumor cells. However, potential redundancies among the various antioxidant systems may constrain this simple approach. Trx1 and thioredoxin reductase 1 (Txnrd1) are upregulated in numerous cancers, and Txnrd1 has been reported to be indispensable for tumorigenesis. However, we report here that genetic ablation of Txnrd1 has no apparent effect on tumor cell behavior based on similar proliferative, clonogenic, and tumorigenic potential. This finding reflects widespread redundancies between the Trx-and GSH-dependent systems based on evidence of a bypass to Txnrd1 deficiency by compensatory upregulation of GSH-metabolizing enzymes. Because the survival and growth of Txnrd1-deficient tumors were strictly dependent on a functional GSH system, Txnrd1 −/− tumors were highly susceptible to experimental GSH depletion in vitro and in vivo. Thus, our findings establish for the first time that a concomitant inhibition of the two major antioxidant systems is highly effective in killing tumor, highlighting a promising strategy to combat cancer. Cancer Res; 70(22); 9505-14. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Loss of Thioredoxin Reductase 1 Renders Tumors Highly Susceptible to Pharmacologic Glutathione Deprivation

et al. 2010

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“…A prooxidative mechanism of tumor killing, through increased ROS production, was proposed. At the expense of NADPH or ascorbate, thioredoxin reductase TrxR would reduce MGd (E 1=2 * À40 mV vs. NHE in N, N'-dimethylformamide), which would in turn transfer electrons to oxygen, producing superoxide and eventually H 2 O 2 (148). The noncompetitive inhibition of thioredoxin reductase and ribonucleotide reductase, resulting in increased levels of ROS, may also play a role.…”

Section: B Texaphyrinsmentioning

confidence: 99%

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

467

689

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Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO 3 _ À , peroxyl radical, and less efficiently H 2 O 2 . By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and=or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877-918.

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“…Previous studies also reported that TrxR1 was one of the genes strongly associated with tumor proliferation in some cancers (23,28). Based on these data, the effect of TrxR inhibitors resveratrol and motexafin gadolinium have been investigated in cancer therapy (22,29,30).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of thioredoxin reductase 1 in human oral squamous cell carcinoma

Uzawa¹

2011

Oncol Rep

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Abstract. Thioredoxin reductase 1 (TrxR1) catalyzes the nicotinamide adenine dinucleotide phosphate-dependent reduction of oxidized thioredoxin (Trx). Trx, which is over-expressed in many human tumors, is a selenocysteine-containing protein associated with cell proliferation and apoptosis inhibition. This selenium-containing redox system regulates the activity of various enzymes and counteracts oxidative stress in cells such as hypoxia and cytotoxic agents. Consequently, TrxR1 could play an important role in tumor progression and resistance to chemotherapy due to its anti-apoptotic functions. To characterize cancer-related gene expression changes in oral squamous cell carcinomas (OSCC), we compared the gene expression profiles in OSCC primary tumors with patientmatched normal oral epithelium. Microarray analysis showed TrxR1 upregulation in primary tumors. Gene ontology analysis showed highly significant cancer-related function. The TrxR1 expression examined by immunohistochemistry was correlated with regional lymph node metastasis (P<0.05) and the clinical stages of 50 patients (P<0.01). Overexpression of TrxR1 could contribute to cancer progression and might be a potential molecular marker for therapy.

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Motexafin Gadolinium, a Tumor-selective Drug Targeting Thioredoxin Reductase and Ribonucleotide Reductase

Cited by 149 publications

References 43 publications

Loss of Thioredoxin Reductase 1 Renders Tumors Highly Susceptible to Pharmacologic Glutathione Deprivation

Loss of Thioredoxin Reductase 1 Renders Tumors Highly Susceptible to Pharmacologic Glutathione Deprivation

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Upregulation of thioredoxin reductase 1 in human oral squamous cell carcinoma

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