Imexon enhances gemcitabine cytotoxicity by inhibition of ribonucleotide reductase

Roman, N.; Samulitis, Betty K.; Wisner, Lee; Landowski, Terry H.; Dorr, Robert T.

doi:10.1007/s00280-010-1306-0

Cited by 7 publications

(5 citation statements)

References 32 publications

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“…The gallium nitrate inhibits the activity of the Ribonucleoside Reductase and this drug has proven a high efficacy to treat Tuberculosis in murine models (Olakanmi et al, 2013 ). While imexon increases oxidative stress in target cells but also inhibits the Ribonucleoside Reductase (Roman et al, 2011 ). Nonetheless, there are not studies using this drug to Tuberculosis treatment.…”

Section: Discussionmentioning

confidence: 99%

Secretome Prediction of Two M. tuberculosis Clinical Isolates Reveals Their High Antigenic Density and Potential Drug Targets

et al. 2017

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The Excreted/Secreted (ES) proteins play important roles during Mycobacterium tuberculosis invasion, virulence, and survival inside the host and they are a major source of immunogenic proteins. However, the molecular complexity of the bacillus cell wall has made difficult the experimental isolation of the total bacterial ES proteins. Here, we reported the genomes of two Beijing genotype M. tuberculosis clinical isolates obtained from patients from Vietnam (isolate 46) and South Africa (isolate 48). We developed a bioinformatics pipeline to predict their secretomes and observed that ~12% of the genome-encoded proteins are ES, being PE, PE-PGRS, and PPE the most abundant protein domains. Additionally, the Gene Ontology, KEGG pathways and Enzyme Classes annotations supported the expected functions for the secretomes. The ~70% of an experimental secretome compiled from literature was contained in our predicted secretomes, while only the 34–41% of the experimental secretome was contained in the two previously reported secretomes for H37Rv. These results suggest that our bioinformatics pipeline is better to predict a more complete set of ES proteins in M. tuberculosis genomes. The predicted ES proteins showed a significant higher antigenic density measured by Abundance of Antigenic Regions (AAR) value than the non-ES proteins and also compared to random constructed secretomes. Additionally, we predicted the secretomes for H37Rv, H37Ra, and two M. bovis BCG genomes. The antigenic density for BGG and for isolates 46 and 48 was higher than the observed for H37Rv and H37Ra secretomes. In addition, two sets of immunogenic proteins previously reported in patients with tuberculosis also showed a high antigenic density. Interestingly, mice infected with isolate 46 showed a significant lower survival rate than the ones infected with isolate 48 and both survival rates were lower than the one previously reported for the H37Rv in the same murine model. Finally, after a druggability analysis of the secretomes, we found potential drug targets such as cytochrome P450, thiol peroxidase, the Ag85C, and Ribonucleoside Reductase in the secreted proteins that could be used as drug targets for novel treatments against Tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Secretome Prediction of Two M. tuberculosis Clinical Isolates Reveals Their High Antigenic Density and Potential Drug Targets

et al. 2017

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“…GEM is a nucleoside analogue of deoxycytidine in which two fluorine atoms have been inserted into the deoxyribose ring . GEM acts on ribonucleotide reductase (RNR) to block DNA replication and repair by binding to RNR active site , and is a broad‐spectrum anticancer drug often used to treat a variety of solid tumors , especially pancreatic cancer . Unfortunately, adjuvant chemotherapy with GEM alone does not significantly improve outcomes because of the development of drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Gemcitabine induces apoptosis and autophagy via the AMPK/mTOR signaling pathway in pancreatic cancer cells

Zhu

Chen

et al. 2018

Biotech and App Biochem

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Gemcitabine (GEM)-based chemotherapy is a commonly used treatment for pancreatic cancer. However, acquired drug resistance, a major problem in pancreatic cancer treatment, causes a reduction in the survival rate of patients with cancer. In this study, we attempted to reveal the molecular mechanism of GEM resistance. Our data showed that GEM treatment inhibits cell growth, induces apoptosis, and activates autophagy via the AMP-activated protein kinase (AMPK) pathway. The combination of GEM treatment and AMPK knockdown resulted in a dramatic increase of apoptosis and inhibition of autophagy. Additionally, inhibition of mammalian target of Rapamycin induced autophagy. Our findings show the potential therapeutic implications of the combined treatment with GEM and AMPK inhibitors for pancreatic cancer.

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“…These two drugs showed synergy in cell cultures and in mice [45]. These two drugs showed synergy in cell cultures and in mice [45].…”

Section: Clinical Studies With Imexonmentioning

confidence: 86%

Chemistry and Pharmacology of Imexon and Related Cyanoaziridines

Wa¹,

Rt²

2012

CMC

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Following the demonstration that addition of a 2-cyano group to aziridines prevented DNA alkylation and thus reduced toxicity, many novel 2-cyanoaziridines were synthesized and evaluated as immunomodulating and antitumor agents. They typically reacted with thiols such as cysteine, depleting them and allowing the accumulation of reactive oxygen species. Two of these compounds, azimexon and ciamexon, showed activity against tumors in clinical trials. Imexon was produced by cyclization of 2-cyanoaziridine-1- carboxamide in the presence of hydroxide ions. The two enantiomers were prepared by a process involving chiral chromatography. They were equipotent against cultured tumor cells. Imexon also reacts with thiols and it is especially potent against multiple myeloma in cell cultures. An efficient chemical synthesis and a lyophilization formulation of imexon as a water soluble, injectible drug, were developed. In Phase I and I/II clinical trials imexon showed hints of activity against a variety of tumors, but a randomized double-blind Phase II trial of imexon plus gemcitabine versus gemcitabine alone in pancreatic cancer showed no enhancement of activity above that of gemcitabine alone. This result was disappointing because in cell culture and mice the two compounds were synergistic. Based on a complete response in a Phase I trial, a new Phase II clinical trial of imexon is underway in non-Hodgkins lymphoma.

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Imexon enhances gemcitabine cytotoxicity by inhibition of ribonucleotide reductase

Cited by 7 publications

References 32 publications

Secretome Prediction of Two M. tuberculosis Clinical Isolates Reveals Their High Antigenic Density and Potential Drug Targets

Secretome Prediction of Two M. tuberculosis Clinical Isolates Reveals Their High Antigenic Density and Potential Drug Targets

Gemcitabine induces apoptosis and autophagy via the AMPK/mTOR signaling pathway in pancreatic cancer cells

Chemistry and Pharmacology of Imexon and Related Cyanoaziridines

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