Cell cycle phase perturbations by 6-diazo-5-oxo-L-norleucine and acivicin in normal and neoplastic human cell lines

Huber, KR; Mayer, EP; Mitchell, DF; Roberts, Joseph

doi:10.1038/bjc.1987.133

Cited by 15 publications

(7 citation statements)

References 8 publications

(2 reference statements)

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“…DON was reported to be effective against human lung, colon, and breast tumor xenografts, inducing tumor regression at high intermittent dosing regimens (25–100 mg/kg IP every 4 days) (41). Mechanistic studies showed DON treatment led to decreased cell proliferation and S phase blocks (42). Animal toxicity studies were performed by the National Cancer Institute using azotomycin, which is metabolized to DON.…”

Section: Clinical Studiesmentioning

confidence: 99%

We're Not “DON” Yet: Optimal Dosing and Prodrug Delivery of6-Diazo-5-oxo-L-norleucine

Lemberg

Vornov

Rais

et al. 2018

Molecular Cancer Therapeutics

168

162

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The broadly active glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) has been studied for 60 years as a potential anticancer therapeutic. Clinical studies of DON in the 1950s using low daily doses suggested antitumor activity, but later phase I and II trials of DON given intermittently at high doses were hampered by dose-limiting nausea and vomiting. Further clinical development of DON was abandoned. Recently, the recognition that multiple tumor types are glutamine-dependent has renewed interest in metabolic inhibitors such as DON. Here, we describe the prior experience with DON in humans. Evaluation of past studies suggests that the major impediments to successful clinical use included unacceptable gastrointestinal (GI) toxicities, inappropriate dosing schedules for a metabolic inhibitor, and lack of targeted patient selection. To circumvent GI toxicity, prodrug strategies for DON have been developed to enhance delivery of active compound to tumor tissues, including the CNS. When these prodrugs are administered in a low daily dosing regimen, appropriate for metabolic inhibition, they are robustly effective without significant toxicity. Patients whose tumors have genetic, metabolic, or imaging biomarker evidence of glutamine dependence should be prioritized as candidates for future clinical evaluations of novel DON prodrugs, given either as monotherapy or in rationally directed pharmacologic combinations. .

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Section: Clinical Studiesmentioning

confidence: 99%

We're Not “DON” Yet: Optimal Dosing and Prodrug Delivery of6-Diazo-5-oxo-L-norleucine

Lemberg

Vornov

Rais

et al. 2018

Molecular Cancer Therapeutics

168

162

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“…In a study which analyzed the effect of DON upon the cell cycle distribution, it was found that this drug causes a striking S-phase block with concurrent increase in G1 and G2-M populations. Of note the effect was differential between the malignant cell lines tested (Redmond colon tumor, A549 lung, CX-1 and CX-2 colon, and LX-1 lung tumor) as compared to normal human embryonic lung fibroblasts IMR-90 [ 102 ]. Studies performed in a neuroblastoma cell line showed that DON targets mitochondria, reporting disruption of mitochondrial internal membrane structures and also the alteration of other organelles such as swelling of endoplasmic reticulum, autophagocytosis of secretory granules, and nuclear condensation or apoptosis [ 103 ].…”

Section: Don (6-diazo-5-oxo-l-norleucine)mentioning

confidence: 99%

Reviving Lonidamine and 6-Diazo-5-oxo-L-norleucine to Be Used in Combination for Metabolic Cancer Therapy

Cervantes-Madrid

Romero

Dueñas‐González

2015

BioMed Research International

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Abnormal metabolism is another cancer hallmark. The two most characterized altered metabolic pathways are high rates of glycolysis and glutaminolysis, which are natural targets for cancer therapy. Currently, a number of newer compounds to block glycolysis and glutaminolysis are being developed; nevertheless, lonidamine and 6-diazo-5-oxo-L-norleucine (DON) are two old drugs well characterized as inhibitors of glycolysis and glutaminolysis, respectively, whose clinical development was abandoned years ago when the importance of cancer metabolism was not fully appreciated and clinical trial methodology was less developed. In this review, a PubMed search using the words lonidamine and 6-diazo-5-oxo-L-norleucine (DON) was undertaken to analyse existing information on the preclinical and clinical studies of these drugs for cancer treatment. Data show that they exhibit antitumor effects; besides there is also the suggestion that they are synergistic. We conclude that lonidamine and DON are safe and potentially effective drugs that need to be reevaluated in combination as metabolic therapy of cancer.

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“…Targeting cancer‐specific biochemical phenotypes, including those determined metabolically, represents an alternative approach to treating patients with lung cancer, the leading cause of cancer deaths in the USA and worldwide . l ‐Glutamine (Gln) is an essential amino acid for non‐small cell lung cancer (NSCLC) growth in vitro and in vivo . Gln has been shown to sustain tumor growth under hypoxia, to mediate K‐RAS‐driven lung cancer growth and to support the autophagy‐mediated prosurvival pathway in B‐RAF V600 ‐driven lung tumors .…”

mentioning

confidence: 99%

“…Inhibition of SLC1A5 attenuates cell growth and mTOR signaling . Although pharmacological strategies to inhibit Gln metabolism using amino acid analogs such as acivicin and 6‐diazo‐5‐oxo‐ l ‐norleucine (DON) have been investigated, the lack of selectivity of these agents has shifted the efforts to developing agents directed at specific nodes of glutamine metabolism instead …”

mentioning

confidence: 99%

Targeting SLC1a5‐mediated glutamine dependence in non‐small cell lung cancer

Hassanein

Qian

Hoeksema

et al. 2015

Intl Journal of Cancer

138

103

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We previously elucidated the pleotropic role of solute carrier family A1 member 5 (SLC1A5) as the primary transporter of glutamine (Gln), a modulator of cell growth and oxidative stress in non-small cell lung cancer (NSCLC). The aim of our study was to evaluate SLC1A5 as a potential new therapeutic target and candidate biomarker predictive of survival and response to therapy. SLC1A5 targeting was examined in a panel of NSCLC and human bronchial cell lines by RNA interference and by a small molecular inhibitor, gamma-L-glutamyl-p-nitroanilide (GPNA). The effects of targeting SLC1A5 on cell growth, Gln uptake, ATP level, autophagy and cell death were examined. Inactivation of SLC1A5 genetically or pharmacologically decreased Gln consumption, inhibited cell growth, induced autophagy and apoptosis in a subgroup of NSCLC cell lines that overexpress SLC1A5. Targeting SLC1A5 function decreased tumor growth in NSCLC xenografts. A multivariate Cox proportional hazards analysis indicates that patients with increased SLC1A5 mRNA expression have significantly shorter overall survival (p =0.01, HR =1.24, 95% CI: 1.05–1.46), adjusted for age, gender, smoking history and disease stage. In an immunohistochemistry study on 207 NSCLC patients, SLC1A5 protein expression remained highly significant prognostic value in both univariate (p < 0.0001, HR =1.45, 95% CI: 1.15–1.50) and multivariate analyses (p =0.04, HR =1.22, 95% CI: 1.01–1.31). These results position SLC1A5 as a new candidate prognostic biomarker for selective targeting of Gln-dependent NSCLC.

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Cell cycle phase perturbations by 6-diazo-5-oxo-L-norleucine and acivicin in normal and neoplastic human cell lines

Cited by 15 publications

References 8 publications

We're Not “DON” Yet: Optimal Dosing and Prodrug Delivery of6-Diazo-5-oxo-L-norleucine

We're Not “DON” Yet: Optimal Dosing and Prodrug Delivery of6-Diazo-5-oxo-L-norleucine

Reviving Lonidamine and 6-Diazo-5-oxo-L-norleucine to Be Used in Combination for Metabolic Cancer Therapy

Targeting SLC1a5‐mediated glutamine dependence in non‐small cell lung cancer

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