Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, in Human Cancer Cells

Tan, Bo; Young, Debra A.; Lu, Zhixin; Wang, Tao; Meier, Timothy I.; Shepard, Robert L.; Roth, Kenneth D.; Zhai, Yan; Huss, Karen; Kuo, Ming‐Shang; Gillig, James R.; Parthasarathy, Saravanan; Burkholder, Timothy P.; Smith, Michèle C.; Geeganage, Sandaruwan; Zhao, Genshi

doi:10.1074/jbc.m112.394510

Cited by 155 publications

(164 citation statements)

References 46 publications

(88 reference statements)

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…The animals (6 animals/group) were dosed orally with 5 and 10 mg/kg of FK866 in 20% Captisol and 25 mM phosphate buffer, pH 2, twice a day for 6 days after tumors reached 500 mm 3 . The tumor volume and body weight were measured twice a week (1). The tumor samples (ϳ50 mg) were homogenized in 1 ml of ice-cold 80% methanol for 30 s with a TissueLyser II and 5-mm stainless steel beads at 4°C.…”

Section: Methodsmentioning

confidence: 99%

“…Similarly, aberrant expression of SIRT, mono(ADPribosyl) transferases, and ADP-ribosyl cyclases can lead to consumption of NAD ϩ in cancer cells (2,4,11). To better understand the metabolic basis of NAMPT inhibition, we have recently shown that inhibition of NAMPT leads to attenuation of glycolysis at the glyceraldehyde-3-phosphate dehydrogenase step (1). The attenuation of glycolysis results in an accumulation of glycolytic intermediates before and at the glyceraldehyde 3-phosphate dehydrogenase step (1).…”

Section: The Nadmentioning

confidence: 99%

“…To better understand the metabolic basis of NAMPT inhibition, we have recently shown that inhibition of NAMPT leads to attenuation of glycolysis at the glyceraldehyde-3-phosphate dehydrogenase step (1). The attenuation of glycolysis results in an accumulation of glycolytic intermediates before and at the glyceraldehyde 3-phosphate dehydrogenase step (1). The attenuation of glycolysis also leads to a decrease of glycolytic intermediates after the glyceraldehyde-3-phosphate dehydrogenase step (1).…”

Section: The Nadmentioning

confidence: 99%

“…The attenuation of glycolysis results in an accumulation of glycolytic intermediates before and at the glyceraldehyde 3-phosphate dehydrogenase step (1). The attenuation of glycolysis also leads to a decrease of glycolytic intermediates after the glyceraldehyde-3-phosphate dehydrogenase step (1). However, due to throughput considerations and technical difficulties, we were unable to separate isomers of glycolytic intermediates, such as glucose 6-phosphate and fructose 6-phosphate, and glyceraldehyde 3-phosphate and dihydroxyacetone phosphate, or their geometrical isomers, such as glucose 1-phosphate and fructose 1-phosphate.…”

Section: The Nadmentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, Leads to Altered Carbohydrate Metabolism in Cancer Cells

Tan

Dong

Shepard

et al. 2015

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: NAMPT inhibition leads to attenuation of glycolysis in cancer cells. Results: NAMPT inhibition also perturbs other carbohydrate metabolism, resulting in elevated fructose 1-phosphate, sedoheptulose 1-phosphate, glyceraldehyde, and erythrose levels. Conclusion: Condensation of dihydroxyacetone phosphate/glyceraldehyde and dihydroxyacetone phosphate/erythrose by aldolase leads to increased fructose 1-phosphate and sedoheptulose 1-phosphate, respectively. Significance: NAMPT plays a key role in regulating glycolysis-related carbohydrate metabolism in cancer cells.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: The Nadmentioning

confidence: 99%

Section: The Nadmentioning

confidence: 99%

Section: The Nadmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, Leads to Altered Carbohydrate Metabolism in Cancer Cells

Tan

Dong

Shepard

et al. 2015

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Importantly, high NAMPT expression has been associated with poor prognosis in different types of cancer, which makes NAMPT a potential therapeutic target 2. It has been shown that NAMPT inhibition leads to a reduction in NAD + intracellular levels, which can induce apoptosis in cancer cells 2a, 3. However, it has also been reported that targeting of NAMPT might lead to side effects such as blindness 4.…”

mentioning

confidence: 99%

A Red‐Light‐Activated Ruthenium‐Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells

et al. 2017

View full text Add to dashboard Cite

We describe two water‐soluble ruthenium complexes, [1]Cl2 and [2]Cl2, that photodissociate to release a cytotoxic nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with a low dose (21 J cm−2) of red light in an oxygen‐independent manner. Using a specific NAMPT activity assay, up to an 18‐fold increase in inhibition potency was measured upon red‐light activation of [2]Cl2, while [1]Cl2 was thermally unstable. For the first time, the dark and red‐light‐induced cytotoxicity of these photocaged compounds could be tested under hypoxia (1 % O2). In skin (A431) and lung (A549) cancer cells, a 3‐ to 4‐fold increase in cytotoxicity was found upon red‐light irradiation for [2]Cl2, whether the cells were cultured and irradiated with 1 % or 21 % O2. These results demonstrate the potential of photoactivated chemotherapy for hypoxic cancer cells, in which classical photodynamic therapy, which relies on oxygen activation, is poorly efficient.

show abstract

Targeting mitochondrial energetics reverses panobinostat‐ and marizomib‐induced resistance in pediatric and adult high‐grade gliomas

et al. 2023

View full text Add to dashboard Cite

In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic activity against pediatric and adult high‐grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain‐penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance. RNA sequencing followed by gene set enrichment analysis (GSEA) was employed to compare the molecular signatures enriched in resistant compared with drug‐naïve cells. The levels of adenosine 5′‐triphosphate (ATP), nicotinamide adenine dinucleotide (NAD)+ content, hexokinase activity, and tricarboxylic acid (TCA) cycle metabolites required for oxidative phosphorylation to meet their bioenergetic needs were analyzed. Here, we report that panobinostat and marizomib significantly depleted ATP and NAD+ content, increased mitochondrial permeability and reactive oxygen species generation, and promoted apoptosis in pediatric and adult glioma cell lines at initial treatment. However, resistant cells exhibited increased levels of TCA cycle metabolites, which required for oxidative phosphorylation to meet their bioenergetic needs. Therefore, we targeted glycolysis and the electron transport chain (ETC) with small molecule inhibitors, which displayed substantial efficacy, suggesting that resistant cell survival is dependent on glycolytic and ETC complexes. To verify these observations in vivo, lonidamine, an inhibitor of glycolysis and mitochondrial function, was chosen. We produced two diffuse intrinsic pontine glioma (DIPG) models, and lonidamine treatment significantly increased median survival in both models, with particularly dramatic effects in panobinostat‐ and marizomib‐resistant cells. These data provide new insights into mechanisms of treatment resistance in gliomas.

show abstract

Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, in Human Cancer Cells

Abstract: Background: NAMPT catalyzes the rate-limiting reaction in converting nicotinamide to NAD ϩ in cancers.

Cited by 155 publications

References 46 publications

Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, Leads to Altered Carbohydrate Metabolism in Cancer Cells

Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, Leads to Altered Carbohydrate Metabolism in Cancer Cells

A Red‐Light‐Activated Ruthenium‐Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells

Targeting mitochondrial energetics reverses panobinostat‐ and marizomib‐induced resistance in pediatric and adult high‐grade gliomas

Contact Info

Product

Resources

About