Targeting the NAD Salvage Synthesis Pathway as a Novel Therapeutic Strategy for Osteosarcomas with Low NAPRT Expression

Franceschini, Natasja; Oosting, Jan; Tamsma, Maud; Niessen, Bertine; Bruijn, Inge H. Briaire-de; Akker, Brendy van den; Kruisselbrink, Alwine B.; Palubeckaitė, Ieva; Bovée, Judith V.M.G.; Cleton‐Jansen, Anne‐Marie

doi:10.3390/ijms22126273

Cited by 10 publications

(14 citation statements)

References 46 publications

(63 reference statements)

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“…NAPRT promoter hypermethylation in cancer is frequently associated with mutations in the protein phosphatase Mg 2+ /Mn 2+ -dependent 1D (PPM1D) or isocitrate dehydrogenase 1 (IDH1) genes, as well as with the epithelial-mesenchymal transition (EMT)-subtype of gastric cancer [ 36 , 37 , 38 ]. Due to their dependency on the Nam salvage pathway for survival, NAPRT-deficient cancers are extremely sensitive to treatment with NAMPT inhibitors [ 39 , 40 ]. On the other hand, NAPRT upregulation confers resistance to NAMPT inhibitors to many malignancies.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

et al. 2022

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NAPRT, the rate-limiting enzyme of the Preiss–Handler NAD biosynthetic pathway, has emerged as a key biomarker for the clinical success of NAMPT inhibitors in cancer treatment. Previous studies found that high protein levels of NAPRT conferred resistance to NAMPT inhibition in several tumor types whereas the simultaneous blockade of NAMPT and NAPRT results in marked anti-tumor effects. While research has mainly focused on NAMPT inhibitors, the few available NAPRT inhibitors (NAPRTi) have a low affinity for the enzyme and have been scarcely characterized. In this work, a collection of diverse compounds was screened in silico against the NAPRT structure, and the selected hits were tested through cell-based assays in the NAPRT-proficient OVCAR-5 ovarian cell line and on the recombinant hNAPRT. We found different chemotypes that efficiently inhibit the enzyme in the micromolar range concentration and for which direct engagement with the target was verified by differential scanning fluorimetry. Of note, the therapeutic potential of these compounds was evidenced by a synergistic interaction between the NAMPT inhibitor FK866 and the new NAPRTi in terms of decreasing OVCAR-5 intracellular NAD levels and cell viability. For example, compound IM29 can potentiate the effect of FK866 of more than two-fold in reducing intracellular NAD levels. These results pave the way for the development of a new generation of human NAPRTi with anticancer activity.

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Section: Introductionmentioning

confidence: 99%

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

et al. 2022

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“…Daporinad has demonstrated excellent tumor regression efficacy in various in vitro and in vivo experiments [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Daporinad completed the phase 2 clinical trial [ 29 , 30 ], and after that, efficacy studies on various tumor targets are ongoing [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Quantitative Analysis of Daporinad (FK866) and Its In Vitro and In Vivo Metabolite Identification Using Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry

Park¹,

Lee²,

Choi³

et al. 2022

Molecules

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Daporinad (FK866) is one of the highly specific inhibitors of nicotinamide phosphoribosyl transferase (NAMPT) and known to have its unique mechanism of action that induces the tumor cell apoptosis. In this study, a simple and sensitive liquid chromatography–quadrupole-time-of-flight–mass spectrometric (LC-qTOF-MS) assay has been developed for the evaluation of drug metabolism and pharmacokinetics (DMPK) properties of Daporinad in mice. A simple protein precipitation method using acetonitrile (ACN) was used for the sample preparation and the pre-treated samples were separated by a C18 column. The calibration curve was evaluated in the range of 1.02~2220 ng/mL and the quadratic regression (weighted 1/concentration2) was used for the best fit of the curve with a correlation coefficient ≥ 0.99. The qualification run met the acceptance criteria of ±25% accuracy and precision values for QC samples. The dilution integrity was verified for 5, 10 and 30-fold dilution and the accuracy and precision of the dilution QC samples were also satisfactory within ±25% of the nominal values. The stability results indicated that Daporinad was stable for the following conditions: short-term (4 h), long-term (2 weeks), freeze/thaw (three cycles). This qualified method was successfully applied to intravenous (IV) pharmacokinetic (PK) studies of Daporinad in mice at doses of 5, 10 and 30 mg/kg. As a result, it showed a linear PK tendency in the dose range from 5 to 10 mg/kg, but a non-linear PK tendency in the dose of 30 mg/kg. In addition, in vitro and in vivo metabolite identification (Met ID) studies were conducted to understand the PK properties of Daporinad and the results showed that a total of 25 metabolites were identified as ten different types of metabolism in our experimental conditions. In conclusion, the LC-qTOF-MS assay was successfully developed for the quantification of Daporinad in mouse plasma as well as for its in vitro and in vivo metabolite identification.

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“…The full search is illustrated in the PRISMA flowchart ( Figure 2 ) . Finally, 70 studies fulfilling the inclusion/exclusion criteria were included in this review [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 6...…”

Section: Resultsmentioning

confidence: 99%

Enhanced Biomimetics of Three-Dimensional Osteosarcoma Models: A Scoping Review

Sandhu,

Bakkalci,

Wei

et al. 2023

Cancers

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This scoping review evaluated 3D osteosarcoma (OS) models’ biomimicry, examining their ability to mimic the tumour microenvironment (TME) and their drug sensitivity. Adhering to PRISMA-ScR guidelines, the systematic search revealed 293 studies, with 70 selected for final analysis. Overall, 64% of 3D OS models were scaffold-based, compared to self-generated spheroid models. Scaffolds generated using native matrix were most common (42%) with collagen I/hydroxyapatite predominating. Both scaffold-based and scaffold-free models were used equally for drug screening. The sensitivity of cancer cells in 3D was reported to be lower than that of cells in 2D in ~90% of the drug screening studies. This correlates with the observed upregulation of drug resistance. OS cells cultured in extracellular matrix (ECM)-mimetic scaffolds and native biomaterials were more resistant than cells in 2D. Co-cultures of OS and stromal cells in 3D models enhanced osteogenic differentiation, ECM remodelling, mineralisation, and angiogenesis, suggesting that tumour–stroma crosstalk promotes disease progression. Seven studies demonstrated selective toxicity of chemotherapeutics towards OS cells while sparing stromal cells, providing useful evidence for developing biomimetic tumour–stroma models to test selective drug toxicity. In conclusion, this review highlights the need to enhance biomimicry in 3D OS models for TME recapitulation, especially in testing novel therapeutics. Future research should explore innovative 3D biomimetic models, biomaterials, and advancements in personalised medicine.

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Targeting the NAD Salvage Synthesis Pathway as a Novel Therapeutic Strategy for Osteosarcomas with Low NAPRT Expression

Cited by 10 publications

References 46 publications

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

Quantitative Analysis of Daporinad (FK866) and Its In Vitro and In Vivo Metabolite Identification Using Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry

Enhanced Biomimetics of Three-Dimensional Osteosarcoma Models: A Scoping Review

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