Objective antitumor activity of acivicin in patients with recurrent CNS malignancies: a Southwest Oncology Group trial.

Taylor, Sarah; Crowley, John; Pollock, Theodore; Eyre, Harmon J.; Jaeckle, C; Hynes, Harry E.; Stephens, RB

doi:10.1200/jco.1991.9.8.1476

Cited by 18 publications

(11 citation statements)

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“…Acivicin efficiently reduced metastatic disease in the B16F10 mouse melanoma model (41) and has been tested in a number of clinical trials for both solid and liquid tumors. The results from these studies show some patient responses in non-small-cell lung carcinoma (42,43) and astrocytoma (44) but no response in relapsed or refractory acute leukemia (45), hepatocellular carcinoma (46), or ovarian carcinoma (47). Intermittent responses, severe central nervous system side effects, and myelosuppression and its reported ability to increase the formation of pancreatic cancer in rats (48) have limited the further development of this compound.…”

Section: Discussionmentioning

confidence: 99%

A Synthetic Lethal Interaction between Glutathione Synthesis and Mitochondrial Reactive Oxygen Species Provides a Tumor-Specific Vulnerability Dependent on STAT3

Garama

Harris

White

et al. 2015

Molecular and Cellular Biology

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e Increased production of mitochondrion-derived reactive oxygen species (ROS) is characteristic of a metabolic shift observed during malignant transformation. While the exact sources and roles of ROS in tumorigenesis remain to be defined, it has become clear that maintaining redox balance is critical for cancer cell proliferation and survival and, as such, may represent a vulnerability that can be exploited therapeutically. STAT3, a latent cytosolic transcription factor activated by diverse cytokines and growth factors, has been shown to exhibit an additional, nontranscriptional function in mitochondria, including modulation of electron transport chain activity. In particular, malignant transformation by Ras oncogenes exploits mitochondrial STAT3 functions. We used mass spectrometry-based metabolomics profiling to explore the biochemical basis for the STAT3 dependence of Ras transformation. We identified the gamma-glutamyl cycle, the production of glutathione, and the regulation of ROS as a mitochondrion-STAT3-dependent pathway in Ras-transformed cells. Experimental inhibition of key enzymes in the glutathione cycle resulted in the depletion of glutathione, accumulation of ROS, oxidative DNA damage, and cell death in an oncogenic Rasand mitochondrial STAT3-dependent manner. These data uncover a synthetic lethal interaction involving glutathione production and mitochondrial ROS regulation in Ras-transformed cells that is governed by mitochondrial STAT3 and might be exploited therapeutically. STAT3 is a latent cytosolic transcription factor activated by phosphorylation on tyrosine 705 in response to many growth factors and cytokines. In normal tissues, STAT3 target genes regulate proliferation, survival, angiogenesis, immune responses, inflammation, and self-renewal (1). STAT3 is also implicated in malignancy (2). Constitutively active STAT3 mutants facilitate experimental transformation (3), and STAT3 is aberrantly phosphorylated or overexpressed in many human tumors. Typically, enhanced STAT3 activation is due to the mutation of upstream tyrosine kinases or receptor tyrosine kinases (e.g., JAK2 in myeloproliferative disease, ALK in some lymphomas, or epidermal growth factor [EGFR] in head and neck cancer) or heightened secretion of cytokines (e.g., interleukin-6 [IL-6] in multiple myeloma or IL-11 in gastric cancer), and STAT3 often has been found to be essential for tumors driven by these stimuli (4). Intriguingly, STAT3 is also required for transformation driven by oncogenic mutations in the Ras-GTPase family in the absence of STAT3 Y705 phosphorylation (5-7). In the context of oncogenic Ras mutations, a mitochondrial pool of STAT3 regulates the activity of the electron transport chain, which is necessary for tumor formation (8). These varied involvements of STAT3 in human cancer have made it an attractive therapeutic candidate (9), although this promise has yet to be fulfilled (10).Metabolic reprogramming is considered a hallmark of cancer. As cells adopt a transformed phenotype, they switch the major source...

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Section: Discussionmentioning

confidence: 99%

A Synthetic Lethal Interaction between Glutathione Synthesis and Mitochondrial Reactive Oxygen Species Provides a Tumor-Specific Vulnerability Dependent on STAT3

Garama

Harris

White

et al. 2015

Molecular and Cellular Biology

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“…Acivicin, the most potent inhibitor of GGT that has been tested clinically, is a neurotoxin (18). The neurotoxicity of the glutamine analogues may be due to interference with glutamine in recycling the neurotransmitter glutamate via the glutamate-glutamine cycle.…”

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confidence: 99%

A Novel, Species-specific Class of Uncompetitive Inhibitors of γ-Glutamyl Transpeptidase

King

West

Cook

et al. 2009

Journal of Biological Chemistry

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Expression of ␥-glutamyl transpeptidase (GGT) in tumors contributes to resistance to radiation and chemotherapy. GGT is inhibited by glutamine analogues that compete with the substrate for the ␥-glutamyl binding site. However, the glutamine analogues that have been evaluated in clinical trials are too toxic for use in humans. We have used high throughput screening to evaluate small molecules for their ability to inhibit GGT and have identified a novel class of inhibitors that are not glutamine analogues. These compounds are uncompetitive inhibitors, binding the ␥-glutamyl enzyme complex. OU749, the lead compound, has an intrinsic K i of 17.6 M. It is a competitive inhibitor of the acceptor glycyl-glycine, which indicates that OU749 occupies the acceptor site while binding to the ␥-glutamyl substrate complex. OU749 is more than 150-fold less toxic than the GGT inhibitor acivicin toward dividing cells. Inhibition of GGT by OU749 is species-specific, inhibiting GGT isolated from human kidney with 7-10-fold greater potency than GGT isolated from rat or mouse kidney. OU749 does not inhibit GGT from pig cells. Human GGT expressed in mouse fibroblasts is inhibited by OU749 similarly to GGT from human cells, which indicates that the species specificity is determined by differences in the primary structure of the protein rather than species-specific, post-translational modifications. These studies have identified a novel class of inhibitors of GGT, providing the basis for further development of a new group of therapeutics that inhibit GGT by a mechanism distinct from the toxic glutamine analogues.

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“…In the report of a phase II clinical study with acivicin, a reversible neurological toxicity was observed in patients with recurrent high-grade astrocytoma, indicating insufficient GGT selectivity and activity of acivicin (Olver et al, 1998). Another study reported that acivicin caused a neurotoxicity that made subjects depressed and hallucinate (Taylor et al, 1991). These negative results found in two clinical studies with acivicin strongly suggest that a high level of selectiveness is required for it to be used as a GGT inhibitor in vivo because these side effects are caused by nonspecific actions of acivicin that inhibits not only GGT activity but also other enzymes involved in nerve stimulation.…”

mentioning

confidence: 99%

Preventive Effect of GGsTop, a Novel and Selective γ-Glutamyl Transpeptidase Inhibitor, on Ischemia/Reperfusion-Induced Renal Injury in Rats

Yamamoto¹,

Watanabe²,

Hiratake³

et al. 2011

J Pharmacol Exp Ther

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GGsTop [2-amino-4-{[3-(carboxymethyl)phenyl](methyl)phosphono}butanoic acid], is a novel, highly selective, and irreversible ␥-glutamyl transpeptidase (GGT) inhibitor with no inhibitory activity on glutamine amidotransferases. In this study, we investigated the effects of treatment with GGsTop on ischemia/reperfusion-induced renal injury in uninephrectomized rats. Ischemic acute kidney injury (AKI) was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion 2 weeks after contralateral nephrectomy. Renal function in vehicle-treated AKI rats markedly decreased at 1 day after reperfusion. Treatment with GGsTop (1 and 10 mg/kg i.v.) 5 min before ischemia attenuated the ischemia/reperfusion-induced renal dysfunction in a dose-dependent manner. Histopathological examination of the kidney of AKI rats revealed severe renal damage, which was significantly suppressed by the GGsTop treatment. In renal tissues exposed to ischemia/reperfusion, GGT activity was markedly increased immediately after reperfusion, whereas renal superoxide production and malondialdehyde level were significantly increased 6 h after reperfusion. These alterations were abolished by the treatment with GGsTop. In addition, renal glutathione content was decreased by the 45-min ischemia, but its level was markedly elevated by the GGsTop treatment. Our results demonstrate that the novel and highly selective GGT inhibitor GGsTop prevents ischemia/ reperfusion-induced AKI. The renoprotective effect of GGsTop seems to be attributed to the suppression of oxidative stress by inhibiting GGT activation, thereby preventing the degradation of glutathione.

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Objective antitumor activity of acivicin in patients with recurrent CNS malignancies: a Southwest Oncology Group trial.

Cited by 18 publications

References 4 publications

A Synthetic Lethal Interaction between Glutathione Synthesis and Mitochondrial Reactive Oxygen Species Provides a Tumor-Specific Vulnerability Dependent on STAT3

A Synthetic Lethal Interaction between Glutathione Synthesis and Mitochondrial Reactive Oxygen Species Provides a Tumor-Specific Vulnerability Dependent on STAT3

A Novel, Species-specific Class of Uncompetitive Inhibitors of γ-Glutamyl Transpeptidase

Preventive Effect of GGsTop, a Novel and Selective γ-Glutamyl Transpeptidase Inhibitor, on Ischemia/Reperfusion-Induced Renal Injury in Rats

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