NMN/NaMN Adenylyltransferase (NMNAT) and NAD Kinase (NADK) Inhibitors: Chemistry and Potential Therapeutic Applications

Petrelli, Riccardo; Felczak, Krzysztof; Cappellacci, Loredana

doi:10.2174/092986711795590048

Cited by 36 publications

(37 citation statements)

References 138 publications

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“…The lowering NADPH levels by inhibition of NADK or G6PD has recently been recognized as a target for cancer drug development (Pandolfi et al, 1995;Kirsch et al, 2009;Petrelli et al, 2011). Although a few inhibitors of NADK have been described, they have lacked potency and have not advanced to preclinical or clinical evaluation (Petrelli et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

et al. 2015

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NAD 1 kinase (NADK) is the only known cytosolic enzyme that converts NAD 1 to NADP 1 , which is subsequently reduced to NADPH. The demand for NADPH in cancer cells is elevated as reducing equivalents are required for the high levels of nucleotide, protein, and fatty acid synthesis found in proliferating cells as well as for neutralizing high levels of reactive oxygen species (ROS). We determined whether inhibition of NADK activity is a valid anticancer strategy alone and in combination with chemotherapeutic drugs known to induce ROS. In vitro and in vivo inhibition of NADK with either small-hairpin RNA or thionicotinamide inhibited proliferation. Thionicotinamide enhanced the ROS produced by several chemotherapeutic drugs and produced synergistic cell kill. NADK inhibitors alone or in combination with drugs that increase ROS-mediated stress may represent an efficacious antitumor combination and should be explored further.

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Section: Discussionmentioning

confidence: 99%

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

et al. 2015

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“…Gallotannin, a polyphenolic compound, inhibits recombinant isoforms of the three NMNATs at micromolar concentrations 7 . Lower inhibitory potency has been reported for five synthetic NAD analogues that have a certain degree of selectivity for the three isoforms 108 . Although these molecules are highly hydrophilic and do not have the potential to be active in vivo, they might be considered as leads in developing potent and isoform-selective NMNAT inhibitors.…”

Section: Nature Reviews | Cancermentioning

confidence: 94%

The NAD metabolome — a key determinant of cancer cell biology

et al. 2012

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NAD is a vital molecule in all organisms. It is a key component of both energy and signal transduction--processes that undergo crucial changes in cancer cells. NAD(+)-dependent signalling pathways are many and varied, and they regulate fundamental events such as transcription, DNA repair, cell cycle progression, apoptosis and metabolism. Many of these processes have been linked to cancer development. Given that NAD(+)-dependent signalling reactions involve the degradation of the molecule, permanent nucleotide resynthesis through different biosynthetic pathways is crucial for incessant cancer cell proliferation. This necessity supports the targeting of NAD metabolism as a new therapeutic concept for cancer treatment.

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“…NadD occupies a central position in bacterial NAD + biosynthesis and is required for both de novo and salvage routes to generate NAD + [14][15][16]. NadD has been recognized as a promising new target for developing novel antibiotics due to its crucial role in synthesizing NAD + [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Biological Activities of the Essential Oil from Erigeron floribundus

et al. 2016

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Erigeron floribundus (Asteraceae) is an herbaceous plant widely used in Cameroonian traditional medicine to treat various diseases of microbial and non-microbial origin. In the present study, we evaluated the in vitro biological activities displayed by the essential oil obtained from the aerial parts of E. floribundus, namely the antioxidant, antimicrobial and antiproliferative activities. Moreover, we investigated the inhibitory effects of E. floribundus essential oil on nicotinate mononucleotide adenylyltransferase (NadD), a promising new target for developing novel antibiotics, and Trypanosoma brucei, the protozoan parasite responsible for Human African trypanosomiasis. The essential oil composition was dominated by spathulenol (12.2%), caryophyllene oxide (12.4%) and limonene (8.8%). The E. floribundus oil showed a good activity against Staphylococcus aureus (inhibition zone diameter, IZD of 14 mm, minimum inhibitory concentration, MIC of 512 µg/mL). Interestingly, it inhibited the NadD enzyme from S. aureus (IC 50 of 98 µg/mL), with no effects on mammalian orthologue enzymes. In addition, T. brucei proliferation was inhibited with IC 50 values of 33.5 µg/mL with the essential oil and 5.6 µg/mL with the active component limonene. The essential oil exhibited strong cytotoxicity on HCT 116 colon carcinoma cells with an IC 50 value of 14.89 µg/mL, and remarkable ferric reducing antioxidant power (tocopherol-equivalent antioxidant capacity, TEAC = 411.9 µmol·TE/g).

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NMN/NaMN Adenylyltransferase (NMNAT) and NAD Kinase (NADK) Inhibitors: Chemistry and Potential Therapeutic Applications

Cited by 36 publications

References 138 publications

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

The NAD metabolome — a key determinant of cancer cell biology

Biological Activities of the Essential Oil from Erigeron floribundus

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