Alpha-Difluoromethylornithine, an Irreversible Inhibitor of Polyamine Biosynthesis, as a Therapeutic Strategy against Hyperproliferative and Infectious Diseases

LoGiudice, Nicole; Le, Linh; Abuan, Irene; Leizorek, Yvette; Roberts, Sigrid C.

doi:10.3390/medsci6010012

Cited by 43 publications

(52 citation statements)

References 108 publications

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“…Polyamines are involved in many cellular processes, including protein synthesis, regulation of gene expression, regulation of ion channels, cell cycling, and many others (20)(21)(22)(23)(24)(25)(26)(27). Synthesis of the three biogenic polyamines putrescine, spermidine, and spermine, can be targeted with drugs such as difluoromethylornithine (DFMO) (28). DFMO is FDA approved and is currently used to treat trypanosomiasis (29)(30)(31) and hirsutism (32).…”

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confidence: 99%

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Polyamine Depletion Abrogates Enterovirus Cellular Attachment

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et al. 2019

J Virol

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Polyamines are small polycationic molecules with flexible carbon chains that are found in all eukaryotic cells. Polyamines are involved in the regulation of many host processes and have been shown to be implicated in viral replication. Depletion of polyamine pools in cells treated with FDA-approved drugs restricts replication of diverse RNA viruses. Viruses can exploit host polyamines to facilitate nucleic acid packaging, transcription, and translation, but other mechanisms remain largely unknown. Picornaviruses, including Coxsackievirus B3 (CVB3), are sensitive to the depletion of polyamines and remain a significant public health threat. We employed CVB3 as a model system to investigate a potential proviral role for polyamines using a forward screen. Passaging CVB3 in polyamine-depleted cells generated a mutation in capsid protein VP3 at residue 234. We show that this mutation confers resistance to polyamine depletion. Through attachment assays, we demonstrate that polyamine depletion limits CVB3 attachment to susceptible cells, which is rescued by incubating virus with polyamines. Furthermore, the capsid mutant rescues this inhibition in polyamine-depleted cells. More divergent viruses also exhibited reduced attachment to polyamine-depleted cells, suggesting that polyamines may facilitate attachment of diverse RNA viruses. These studies inform additional mechanisms of action for polyamine-depleting pharmaceuticals, with implications for potential antiviral therapies. IMPORTANCE Enteroviruses are significant human pathogens that can cause severe disease. These viruses rely on polyamines, small positively charged molecules, for robust replication, and polyamine depletion limits infection in vitro and in vivo. The mechanisms by which polyamines enhance enteroviral replication are unknown. Here, we describe how Coxsackievirus B3 (CVB3) utilizes polyamines to attach to susceptible cells and initiate infection. Using a forward genetic screen, we identified a mutation in a receptor-binding amino acid that promotes infection of polyamine-depleted cells. These data suggest that pharmacologically inhibiting polyamine biosynthesis may combat virus infection by preventing virus attachment to susceptible cells.

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confidence: 99%

“…DFMO is FDA approved and is currently used to treat trypanosomiasis (29)(30)(31) and hirsutism (32). DFMO specifically inhibits ODC1, a rate-limiting enzyme at the beginning of the polyamine synthesis pathway (28). We previously demonstrated that RNA viruses utilize cellular polyamines for their replication (33,34).…”

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confidence: 99%

Polyamine Depletion Abrogates Enterovirus Cellular Attachment

Kicmal

Tate

Dial

et al. 2019

J Virol

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“…As chemoprevention involves the long-term administration of a natural or synthetic compound to healthy individuals with the goal of preventing or delaying the onset of disease, the minimization of potential side effects is critical. The overall safety of DFMO has been well established, and it currently retains orphan drug FDA status with approval for the treatment of human African trypanosomiasis and female hirsutism [ 53 ]. Although its long-term use was initially associated with a dose-related, reversible ototoxicity, anemia, and mild gastrointestinal side effects, dose de-escalation studies focusing on prevention rather than cancer treatment revealed that DFMO dosage could be reduced to that which minimizes these off-target effects while effectively reducing colorectal mucosa polyamine levels in patients susceptible to colorectal cancer [ 13 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Curcumin mediates polyamine metabolism and sensitizes gastrointestinal cancer cells to antitumor polyamine-targeted therapies

et al. 2018

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Curcumin, a natural polyphenol that contributes to the flavor and yellow pigment of the spice turmeric, is known for its antioxidant, anti-inflammatory, and anticarcinogenic properties. Capable of affecting the initiation, promotion, and progression of carcinogenesis through multiple mechanisms, curcumin has potential utility for both chemoprevention and chemotherapy. Previous studies demonstrated that curcumin can inhibit ornithine decarboxylase (ODC) activity in human leukemia and breast cancer cells, and pretreatment with dietary curcumin blocks carcinogen-induced ODC activity in rodent models of skin, colon, and renal cancer. The current study investigated the regulation of polyamine metabolism in human gastric and colon carcinoma cell lines in response to curcumin. Curcumin treatment significantly induced spermine oxidase (SMOX) mRNA and activity, which results in the generation of hydrogen peroxide, a source of ROS. Simultaneously, curcumin down regulated spermidine/spermine N1-acetyltransferase (SSAT) activity and the biosynthetic enzymes ODC and S-adenosylmethionine decarboxylase (SAMDC), thereby diminishing intracellular polyamine pools. Combination treatments using curcumin with the ODC inhibitor 2-difluoromethylornithine (DFMO), an agent currently in clinical chemoprevention trials, significantly enhanced inhibition of ODC activity and decreased growth of GI cancer cell lines beyond that observed with either agent alone. Similarly, combining curcumin with the polyamine analogue bis(ethyl)norspermine enhanced growth inhibition that was accompanied by enhanced accumulation of the analogue and decreased intracellular polyamine levels beyond those observed with either agent alone. Importantly, cotreatment with curcumin permitted the lowering of the effective dose of ODC inhibitor or polyamine analogue. These studies provide insight into the polyamine-related mechanisms involved in the cancer cell response to curcumin and its potential as a chemopreventive or chemotherapeutic agent in the GI tract.

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“…Where I pC refers to the cathodic peak current, n is the number of electron transfer (n = 1), A represents the surface area of the electrode (cm 2 ), D 0 is the diffusion coefficient ð7:6 � 10 À 6 cm 2 s À 1 Þ, u is the scan rate and C 0 is the concentration of K 3 [Fe(CN) 6 ] ð5 � 10 À 6 mol:cm À 3 Þ. Subsequently, from the slope of plotting I pC versus square root of scan rate u 1 = 2 !…”

Section: Electrochemical Performance Of the Modified Electrodementioning

confidence: 99%

“…DFMO is the only new treatment since last seven decades, for the second stage African Trypanosomiasis (HAT, also known as sleeping sickness) [4,5]. In addition, it has been applied for treatment of the facial hirsutism in women [6]. Since the 1980s, studies have shown that DFMO can aid in some chemoprevention by decreasing the polyamine levels [7].…”

Section: Introductionmentioning

confidence: 99%

Electrochemical Derivatization of Acetaminophen for Indirect Determination of Eflornithine Using β‐CD Modified Glassy Carbon Electrode

et al. 2019

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In the present work, the oxidation of acetaminophen in the absence and presence of eflornithine was electrochemically investigated by means of cyclic voltammetry at a glassy carbon electrode (GCE). Our results indicate that N‐acetyl‐p‐benzoquinone imine (NAPQI) produced from two‐electron electrochemical oxidation of acetaminophen participates in a Michael addition reaction with eflornithine via an ECE mechanism. This fact was used for the determination of eflornithine using differential pulse voltammetry (DPV) technique on the surface of β‐Cyclodextrin modified glassy carbon (β‐CD/GC) electrode. β‐CD/GC electrode was prepared through an electrodeposition procedure and characterized by Fourier‐transform infrared spectroscopy (FT‐IR), Cyclic Voltammetry (CV), Field Emission Scanning Electron Microscopy (FESEM) and Energy‐dispersive X‐ray spectroscopy (EDS) techniques. Under optimum conditions, the β‐CD/GC electrode showed a good linearity as a function of the eflornithine concentration over the range from 5 to 100 μM with detection limit and quantification limit of 1.94 and 5.8 μM, respectively. Finally, the proposed protocol was confirmed to be successful in determination of eflornithine in human urine samples with good recovery, ranging from 97.2 % to 104.8 %.

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Alpha-Difluoromethylornithine, an Irreversible Inhibitor of Polyamine Biosynthesis, as a Therapeutic Strategy against Hyperproliferative and Infectious Diseases

Cited by 43 publications

References 108 publications

Polyamine Depletion Abrogates Enterovirus Cellular Attachment

Polyamine Depletion Abrogates Enterovirus Cellular Attachment

Curcumin mediates polyamine metabolism and sensitizes gastrointestinal cancer cells to antitumor polyamine-targeted therapies

Electrochemical Derivatization of Acetaminophen for Indirect Determination of Eflornithine Using β‐CD Modified Glassy Carbon Electrode

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