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CD38 regulates extracellular but not intracellular NAD + levels in RPWE1 cells. a Western blots demonstrate doxycyline (Dox) induced expression of wild-type (WT) or mutant (E226Q) CD38 in RWPE1 cells. Tubulin serves as a loading control. b Cell proliferation assay over 4 days in culture in the presence or absence of 20 ng/mL Dox. Relative cell number was assessed by measuring DNA fluorescence at 465 nm. 3-6 replicate wells per group per time point were measured. Plot shows mean ± standard error of the mean (SEM). c, d NAD + and NADH levels were measured relative to total protein in each sample and presented relative to no Dox (non-induced) sample. Mean ± SEM of four replicates is shown. e NAD + :NADH ratio is calculated based on results shown in c and d. Mean ± SEM of four replicates is shown. f Cells were treated with Triton X-100 (TX-100) to permeabilize cells followed by NAD + measurements. NAD + /protein is shown relative to no Dox. Mean ± SEM of four replicates is shown. g-i RWPE1 cells were treated with increasing concentrations of FK866 followed by NAD + (g) and NADH (h) measurements. Mean ± SEM of four replicates is shown. Newman-Keuls Multiple Comparison Test. i Cell proliferation assay over 4 days in culture in the presence of the indicated concentrations of FK866. DNA fluorescence represents relative cell number. 3-6 replicate wells per group per time point were measured. Plot shows mean ± standard error of the mean (SEM). j Relative NAD + /protein levels in the media 30 min after the addition of 800 nM exogenous NAD +. Mean ± SEM of four replicates is shown
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Background
Cancer cell metabolism requires sustained pools of intracellular nicotinamide adenine dinucleotide (NAD⁺) which is maintained by a balance of NAD⁺ hydrolase activity and NAD⁺ salvage activity. We recently reported that human prostate cancer can be initiated following oncogene expression in progenitor-like luminal cells marked by low expr...
Contexts in source publication
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... prostate epithelial cells, we generated an inducible vector to engineer over-expression of wild-type CD38 or an NAD + hydrolase-deficient point mutant [60] of CD38 (E226Q). We introduced wild-type or mutant CD38 into benign RWPE1 cells. Addition of 20 ng/ml doxycyc- line (Dox) was sufficient to induce CD38 expression within 48 h by western blot (Fig. 4a). Higher levels of Dox caused a significant reduction in intracellular NAD + levels in non-transduced cell lines (Additional file 4) and have been associated with metabolic changes [61], so we chose to carry out our studies using 20 ng/ml Dox. The alamar- Blue assay is often used to measure cell viability and pro- liferation in culture ...
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... influence colorimetric changes used to quantify cell num- ber. As an alternative to alamarBlue, we used DNA quan- tification to measure relative cell number in order to evaluate cell proliferation over 4 days in culture. With both approaches, we found no significant difference in cell proliferation following expression of wild-type or mutant CD38 (Fig. 4b, Additional file 5a). We utilized an NAD + / NADH cycling assay to measure changes in intracellular NAD + and NADH levels upon expression of CD38 relative to total cellular protein. Surprisingly, addition of Dox was not sufficient to alter intracellular NAD + , NADH, or NAD + :NADH ratio (Fig. 4c-e). Results were replicated using LNCaP ...
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... following expression of wild-type or mutant CD38 (Fig. 4b, Additional file 5a). We utilized an NAD + / NADH cycling assay to measure changes in intracellular NAD + and NADH levels upon expression of CD38 relative to total cellular protein. Surprisingly, addition of Dox was not sufficient to alter intracellular NAD + , NADH, or NAD + :NADH ratio (Fig. 4c-e). Results were replicated using LNCaP and DU145 prostate cancer cells expressing wild-type or mutant CD38 (Additional file 5b- e, Additional file 6a, b). CD38-expressing cells did not show an upregulation of NAMPT or NAPRT, two enzymes that can regenerate NAD + from precursors (Additional file 7a, b). Cells were treated with Triton-X100 ...
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... of NAMPT or NAPRT, two enzymes that can regenerate NAD + from precursors (Additional file 7a, b). Cells were treated with Triton-X100 to permeabilize cell membranes for 15 min prior to NAD + /NADH measurements. Following permeabilization, cells expressing wild-type CD38, but not mutant CD38, demonstrated a dramatic reduction in NAD + levels (Fig. 4f, Additional file 6: Figure S6c,d). These findings suggest that wild-type CD38 exhibits NAD + hydrolase activity in permeabilized but not intact cells. Taken together, we find a lack of evidence to support CD38 as a significant regula- tor of intracellular NAD + levels or cell proliferation during short-term culture. Considerable ...
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... we find a lack of evidence to support CD38 as a significant regula- tor of intracellular NAD + levels or cell proliferation during short-term culture. Considerable depletion of intracellular NAD + and NADH levels by FK866, a small molecule in- hibitor of NAMPT, was sufficient to impair cell prolifera- tion of RWPE1, LNCaP, DU145, and PC-3 cells (Fig. 4g-i, Additional file 8a-i), similar to what has been reported for LNCaP and PC-3 cells ...
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... expression of wild-type CD38 signifi- cantly reduced extracellular NAD + levels, while no significant differences were observed in cells express- ing mutant CD38 (Fig. 4j, Additional file 6e, f ). Intra- cellular levels of NAD + did not increase after adding exogenous NAD + to the media (Additional file ...
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... showed that CD38 over-expression reduced intracellular NAD + levels by approximately 35% and this was associated with a re- duced growth rate in vitro [70]. However, our results using NAMPT inhibitor FK866 indicate that even a 50% reduction in NAD + levels is not sufficient to im- pair cell proliferation of multiple human prostate cell lines (Fig. 4g-i, Additional file 8). Using mouse models, researchers have demonstrated increased NAD + levels in certain tissues lacking CD38 when compared to wild-type mice [28], which we validated in liver tissue (Additional file 10a). Interestingly, when NAD + levels were measured in various tissues from wild-type or knockout mice, including liver, adipose tissue, ...
Citations
... The net effect is that in the presence of elevated extracellular NAD + , IL-13 leads to reduced inflammatory response. Many of the extracellular activities of NAD + are facilitated by the effects of the cell surface enzyme CD38 [60]. CD38 is an ectoenzyme found on immune cells that converts NAD + into cADPR, ADPR, and NAM that leads to immune cell suppression [61]. ...
The essential role of nicotinamide adenine dinucleotide+ (NAD+) in redox reactions during oxidative respiration is well known, yet the coenzyme and regulator functions of NAD+ in diverse and important processes are still being discovered. Maintaining NAD+ levels through diet is essential for health. In fact, the United States requires supplementation of the NAD+ precursor niacin into the food chain for these reasons. A large body of research also indicates that elevating NAD+ levels is beneficial for numerous conditions, including cancer, cardiovascular health, inflammatory response, and longevity. Consequently, strategies have been created to elevate NAD+ levels through dietary supplementation with NAD+ precursor compounds. This paper explores current research regarding these therapeutic compounds. It then focuses on the NAD+ regulation of IL-13 signaling, which is a research area garnering little attention. IL-13 is a critical regulator of allergic response and is associated with Parkinson’s disease and cancer. Evidence supporting the notion that increasing NAD+ levels might reduce IL-13 signal-induced inflammatory response is presented. The assessment is concluded with an examination of reports involving popular precursor compounds that boost NAD+ and their associations with IL-13 signaling in the context of offering a means for safely and effectively reducing inflammatory response by IL-13.
... In prostate cancer, cellular NAD + stores are elevated as a consequence of promoter methylation silencing of the CD38 gene, the main NADase in cells. This dysregulation of NAD + metabolism contributes to prostate cancer progression, possibly involving SIRT7 [104,105]. Notably, SIRT7 plays a role in promoting androgen-triggered autophagy, which contributes to cell growth, metastasis, and radiation resistance in prostate cancer. This effect is mediated by SIRT7 regulation of androgen receptor (AR) activity through SMAD4 [48]. ...
Sirtuin 7 (SIRT7) is a member of the sirtuin family and has emerged as a key player in numerous cellular processes. It exhibits various enzymatic activities and is predominantly localized in the nucleolus, playing a role in ribosomal RNA expression, DNA damage repair, stress response and chromatin compaction. Recent studies have revealed its involvement in diseases such as cancer, cardiovascular and bone diseases, and obesity. In cancer, SIRT7 has been found to be overexpressed in multiple types of cancer, including breast cancer, clear cell renal cell carcinoma, lung adenocarcinoma, prostate adenocarcinoma, hepatocellular carcinoma, and gastric cancer, among others. In general, cancer cells exploit SIRT7 to enhance cell growth and metabolism through ribosome biogenesis, adapt to stress conditions and exert epigenetic control over cancer-related genes. The aim of this review is to provide an in-depth understanding of the role of SIRT7 in cancer carcinogenesis, evolution and progression by elucidating the underlying molecular mechanisms. Emphasis is placed on unveiling the intricate molecular pathways through which SIRT7 exerts its effects on cancer cells. In addition, this review discusses the feasibility and challenges associated with the development of drugs that can modulate SIRT7 activity.
... This activity is very important for maintaining the dynamic balance of NAD, nicotinamide, and other substances in the body (37). It is also worth noting that, unlike most tumors, CD38 has been detected to be down-regulated in PCa, especially in advanced castration-resistant prostate cancer (CRPC), which may be due to methylation silencing (38,39). Additionally, some studies have revealed that invasive PCa and unfavorable results are frequently linked to decreased CD38 expression (40). ...
Background:
The composition of the tumor microbial microenvironment participates in the whole process of tumor disease. However, due to the limitations of the current technical level, the depth and breadth of the impact of microorganisms on tumors have not been fully recognized, especially in prostate cancer (PCa). Therefore, the purpose of this study is to explore the role and mechanism of the prostate microbiome in PCa based on bacterial lipopolysaccharide (LPS)-related genes by means of bioinformatics.
Methods:
The Comparative Toxicogenomics Database (CTD) was used to find bacterial LPS- related genes. PCa expression profile data and clinical data were acquired from TCGA, GTEx, and GEO. The differentially expressed LPS-related hub genes (LRHG) were obtained by Venn diagram, and gene set enrichment analysis (GSEA) was used to investigate the putative molecular mechanism of LRHG. The immune infiltration score of malignancies was investigated using single-sample gene set enrichment analysis (ssGSEA). Using univariate and multivariate Cox regression analysis, a prognostic risk score model and nomogram were developed.
Results:
6 LRHG were screened. LRHG were involved in functional phenotypes such as tumor invasion, fat metabolism, sex hormone response, DNA repair, apoptosis, and immunoregulation. And it can regulate the immune microenvironment in the tumor by influencing the antigen presentation of immune cells in the tumor. And a prognostic risk score and the nomogram, which were based on LRHG, showed that the low-risk score has a protective effect on patients.
Conclusion:
Microorganisms in the PCa microenvironment may use complex mechanism and networks to regulate the occurrence and development of PCa. Bacterial lipopolysaccharide-related genes can help build a reliable prognostic model and predict progression-free survival in patients with prostate cancer.
... We next evaluated the presence of HLA-A methylation in primary and metastatic tumor samples (Fig. 2d). We employed COMPARE-MS, a method that has been previously used to measure methylation in prostate cancer biopsies [30][31][32][33][34] . HLA-A methylation was either not detected or detected at very low levels in benign samples. ...
... After co-culture, T-cell activation markers were measured by flow cytometry in T-cells from each coculture treatment condition (Fig. 6b). We found that PSMA [27][28][29][30][31][32][33][34][35][36][37][38] tetramer-positive (PSMA + ) CD8 + T-cells that were co-cultured with LNCaP cells treated with any DNMT or HDAC inhibitor increased in frequency and expressed increased levels of activation markers CD69 and LFA-1 compared to those co-cultured with DMSO-treated LNCaP cells. These T-cells also expressed increased levels of granzyme B and interferon-γ (IFN-γ), markers indicative of T-cell stimulation and differentiation into cytotoxic T-cells. ...
... Patient samples used in this analysis were previously described 30,33 . COMPARE-MS was performed as previously described 30 Each core was cut into~1 mm 2 by 1 mm 2 cubes. ...
Downregulation of HLA class I (HLA-I) impairs immune recognition and surveillance in prostate cancer and may underlie the ineffectiveness of checkpoint blockade. However, the molecular mechanisms regulating HLA-I loss in prostate cancer have not been fully explored. Here, we conducted a comprehensive analysis of HLA-I genomic, epigenomic and gene expression alterations in primary and metastatic human prostate cancer. Loss of HLA-I gene expression was associated with repressive chromatin states including DNA methylation, histone H3 tri-methylation at lysine 27, and reduced chromatin accessibility. Pharmacological DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibition decreased DNA methylation and increased H3 lysine 27 acetylation and resulted in re-expression of HLA-I on the surface of tumor cells. Re-expression of HLA-I on LNCaP cells by DNMT and HDAC inhibition increased activation of co-cultured prostate specific membrane antigen (PSMA)27-38-specific CD8⁺ T-cells. HLA-I expression is epigenetically regulated by functionally reversible DNA methylation and chromatin modifications in human prostate cancer. Methylated HLA-I was detected in HLA-Ilow circulating tumor cells (CTCs), which may serve as a minimally invasive biomarker for identifying patients who would benefit from epigenetic targeted therapies.
... In addition to the extracellular adenosine, NAD+ is another critical factor for immune escape. It has been confirmed to participate in a series of reactions, like cell proliferation, leucocyte differentiation, as well as function [80][81][82]. However, CD38 is an ectoenzyme and transmits NAD+ to ADP-ribose (ADPR) and cADPR. ...
The discovery of immune checkpoint inhibitors (ICIs) has now been universally acknowledged as a significant breakthrough in tumor therapy after the targeted treatment of checkpoint molecules: anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on several cancer types achieved satisfying results. However, there are still quite a lot of patients suffering from severe side effects and ineffective treatment outcomes. Although the current ICI therapy is far from satisfying, a series of novel immune checkpoint molecules with remarkable preclinical and clinical benefits are being widely investigated, like the V-domain Ig suppressor of T cell activation (VISTA), which can also be called PD-1 homolog (PD-1H), and ectonucleotidases: CD39, CD73, and CD38, which belong to the ribosyl cyclase family, etc. In this review, we systematically summarized and discussed these molecules' biological structures, molecular features, and the corresponding targeted drugs, aiming to help the in-depth understanding of immune checkpoint molecules and promote the clinical practice of ICI therapy.
... 9 There is no evidence that NAD can be generated extracellularly except during stress/inflammation, where intracellular NAD might move into extracellular space by active exocytosis, diffusion through membrane transporters, or by cell damage and death. [32][33][34][35][36] Although extracellular NAD+ is present in low amounts, recent studies show that mammalian cells can import low concentrations of NAD+ across the membrane. 29,[37][38][39] This suggests that an unidentified transporter of intact NAD+ might exist. ...
Cluster of differentiation 38 (CD38) is an ecto-enzyme expressed primarily on immune cells that metabolizes nicotinamide adenine dinucleotide (NAD+) to adenosine diphosphate ribose or cyclic ADP-ribose and nicotinamide. Other substrates of CD38 include nicotinamide adenine dinucleotide phosphate and nicotinamide mononucleotide, a critical NAD+ precursor in the salvage pathway. NAD+ is an important coenzyme involved in several metabolic pathways and is a required cofactor for the function of sirtuins (SIRTs) and poly (adenosine diphosphate-ribose) polymerases. Declines in NAD+ levels are associated with metabolic and inflammatory diseases, aging, and neurodegenerative disorders. To inhibit CD38 enzyme activity and boost NAD+ levels, we developed TNB-738, an anti-CD38 biparatopic antibody that pairs two non-competing heavy chain-only antibodies in a bispecific format. By simultaneously binding two distinct epitopes on CD38, TNB-738 potently inhibited its enzymatic activity, which in turn boosted intracellular NAD+ levels and SIRT activities. Due to its silenced IgG4 Fc, TNB-738 did not deplete CD38-expressing cells, in contrast to the clinically available anti-CD38 antibodies, daratumumab, and isatuximab. TNB-738 offers numerous advantages compared to other NAD-boosting therapeutics, including small molecules, and supplements, due to its long half-life, specificity, safety profile, and activity. Overall, TNB-738 represents a novel treatment with broad therapeutic potential for metabolic and inflammatory diseases associated with NAD+ deficiencies.
Abbreviations: 7-AAD: 7-aminoactinomycin D; ADCC: antibody dependent cell-mediated cytotoxicity; ADCP: antibody dependent cell-mediated phagocytosis; ADPR: adenosine diphosphate ribose; APC: allophycocyanin; cADPR: cyclic ADP-ribose; cDNA: complementary DNA; BSA: bovine serum albumin; CD38: cluster of differentiation 38; CDC: complement dependent cytotoxicity; CFA: Freund’s complete adjuvant; CHO: Chinese hamster ovary; CCP4: collaborative computational project, number 4; COOT: crystallographic object-oriented toolkit; DAPI: 4′,6-diamidino-2-phenylindole; DNA: deoxyribonucleic acid; DSC: differential scanning calorimetry; 3D: three dimensional; εNAD+: nicotinamide 1,N6-ethenoadenine dinucleotide; ECD: extracellular domain; EGF: epidermal growth factor; FACS: fluorescence activated cell sorting; FcγR: Fc gamma receptors; FITC: fluorescein isothiocyanate; HEK: human embryonic kidney; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; IgG: immunoglobulin; IFA: incomplete Freund’s adjuvant; IFNγ: Interferon gamma; KB: kinetic buffer; kDa: kilodalton; KEGG: kyoto encyclopedia of genes and genomes; LDH: lactate dehydrogenase; M: molar; mM: millimolar; MFI: mean fluorescent intensity; NA: nicotinic acid; NAD: nicotinamide adenine dinucleotide; NADP: nicotinamide adenine dinucleotide phosphate; NAM: nicotinamide; NGS: next-generation sequencing; NHS/EDC: N-Hydroxysuccinimide/ ethyl (dimethylamino propyl) carbodiimide; Ni-NTA: nickel-nitrilotriacetic acid; nL: nanoliter; NK: natural killer; NMN: nicotinamide mononucleotide; OD: optical density; PARP: poly (adenosine diphosphate-ribose) polymerase; PBS: phosphate-buffered saline; PBMC: peripheral blood mononuclear cell; PDB: protein data bank; PE: phycoerythrin; PISA: protein interfaces, surfaces, and assemblies: PK: pharmacokinetics; mol: picomolar; RNA: ribonucleic acid; RLU: relative luminescence units; rpm: rotations per minute; RU: resonance unit; SEC: size exclusion chromatography; SEM: standard error of the mean; SIRT: sirtuins; SPR: surface plasmon resonance; µg: microgram; µM: micromolar; µL: microliter
... This observation, however, was not further followed up and investigated within our research group. Findings from recent studies provided important insights in relation to the role of CD38 in prostate cancer (Liu et al., 2016;Chmielewski et al., 2018;Mottahedeh et al., 2018;Guo et al., 2021). These recent findings suggest that silencing CD38 (through methylation) may confer survival advantage to tumor-initiating progenitor cells or proliferative cancer cells by increasing NAD + availability and mitochondrial function (Chiarugi et al., 2012;Camacho-Pereira et al., 2016;Liu et al., 2016;Chmielewski et al., 2018;Mottahedeh et al., 2018). ...
... Findings from recent studies provided important insights in relation to the role of CD38 in prostate cancer (Liu et al., 2016;Chmielewski et al., 2018;Mottahedeh et al., 2018;Guo et al., 2021). These recent findings suggest that silencing CD38 (through methylation) may confer survival advantage to tumor-initiating progenitor cells or proliferative cancer cells by increasing NAD + availability and mitochondrial function (Chiarugi et al., 2012;Camacho-Pereira et al., 2016;Liu et al., 2016;Chmielewski et al., 2018;Mottahedeh et al., 2018). These studies also suggest CD38 expression at the bulk tissue level was progressively lower in more advanced castration-resistant prostate cancers. ...
... Functional studies focusing on CD38 in prostate cancer have relied on prostate cancer cell lines. Prostate cancer cell lines are negative for CD38 and have been used to investigate the function of CD38 following gene overexpression (Chmielewski et al., 2018;Mottahedeh et al., 2018). These two studies reported contradictory findings with regard to the regulation of intracellular NAD + by CD38 (Chmielewski et al., 2018;Mottahedeh et al., 2018). ...
Nicotinamide adenine dinucleotide (NAD ⁺ ) is an essential molecule for living organisms. CD38 is a key NAD ⁺ -dependent enzyme which breaks down NAD ⁺ to cyclic ADP-ribose (ADPR) and nicotinamide (NAM, vitamin B3), and NAM can be recycled to synthesize NAD ⁺ . CD38 expression is consistently silenced by methylation in prostate cancer and progressively downregulated in advanced castration-resistant prostate cancer, suggesting a connection between NAD ⁺ and prostate carcinogenesis as well as prostate cancer progression. However, the functional interplay between NAD ⁺ , CD38, and NAM remains largely uncharacterized in prostate cancer cells. In this study, we generated stable LNCaP95 cell clones expressing varying levels of CD38 upon induction by doxycycline. We demonstrate that CD38 overexpression resulted in growth suppression and apoptosis accompanied by cleavage of poly (ADP-ribose) polymerase 1 (PARP1). CD38 overexpression also dramatically reduced intracellular NAD ⁺ levels and decreased mitochondrial respiration as measured by oxygen consumption rate. We further show that some but not all of these CD38-induced phenotypes could be rescued by exogenous NAM. Treatment of cells with NAM rescued CD38-induced apoptosis and mitochondrial stress but did not restore intracellular NAD ⁺ levels. We also found that NAM demonstrated biphasic effect on mitochondria function, a finding that can be explained by the dual role of NAM as both a precursor of NAD ⁺ and also as a suppressor of a number of NAD ⁺ -dependent enzymes. Collectively, these findings provide additional insight supporting the functional relevance of CD38 loss in prostate cancer by linking cell-autonomous regulation of mitochondrial function and prostate cancer.
... This is because cancer metabolism-related agents can potentially enhance the therapeutic effect when combined with conventional chemotherapies [6,7]. Recently, the biochemical pathway of nicotinamide adenine dinucleotide (NAD) has received much attention among these cancer metabolism researches [8][9][10][11][12][13][14]. The NAD is a major co-enzyme of glyceraldehyde-3-phosphate dehydrogenase (G3PDH) in glycolysis, a major glucose metabolic pathway in cancer cells, and is also involved in tricarboxylic acid (TCA) cycle and oxidative phosphorylation in cancer cells [15,16]. ...
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.
... In vivo, mouse models deficient in the expression of CD38 fed with a high-fat diet were protected against cancer development and had greater longevity in comparison with wild-type control [66]. Furthermore, increased CD38 activity in these tumor cells resulted in decreased cellular NAD + , a reduction in cell growth, and an increase in apoptosis and cell senescence [66,81]. ...
... As reported by Mottahedeh et al., CD38 mRNA was reduced in castration-resistant metastatic prostate cancer compared with localized prostate cancer, while CD38 protein expression was inversely correlated with disease recurrence. CD38 overexpression in this cancer led to decreased extracellular but not intracellular NAD + levels, although NAD + levels did not clarify the functional relevance of this extracellular NAD + reduction in these studies [81]. Another study confirmed that CD38 expression is inversely correlated with tumor progression in prostate cancer and that this corresponds to increased levels of NAD + in the tumor [44]. ...
The type II transmembrane glycoprotein CD38 has recently been implicated in regulating metabolism and the pathogenesis of multiple conditions, including aging, inflammation and cancer. CD38 is overexpressed in several tumor cells and microenvironment tumoral cells, associated to migration, angiogenesis, cell invasion and progression of the disease. Thus, CD38 has been used as a progression marker for different cancer types as well as in immunotherapy. This review focuses on describing the involvement of CD38 in various non-hematopoietic cancers.
... Cells, especially cancer cells, release intracellular NAD + into the culture medium, indicating that NAD + may serve as an autocrine or paracrine signaling molecule for nearby cells. 23 Extracellular NAD + restores intracellular NAD + pools and helps counteract cell the death induced by NAMPT inhibition. 7,8,24,25 Extracellular NAD + is mainly consumed through the action of CD38, a ubiquitously expressed transmembrane NAD + glycohydrolase. ...
... 7,8,24,25 Extracellular NAD + is mainly consumed through the action of CD38, a ubiquitously expressed transmembrane NAD + glycohydrolase. 23,26 CD38 expression delays cancer development by lowering NAD + levels, with a reduction in cell metabolism that leads to cell cycle arrest. 27 Extracellular NAD + also plays important roles in immune modulation. ...
... 300 However, CD38 expression specifically leads to the consumption of extracellular NAD + and not intracellular NAD + in prostate cancer cells. 23 Moreover, CD38 also consumes extracellular NMN, generating NAM, which can be converted to NAD + through NAMPT and NMNAT after crossing the plasma membrane. 123 Another important membrane-bound enzyme that degrades extracellular NAD + is CD73. ...
NAD ⁺ was discovered during yeast fermentation, and since its discovery, its important roles in redox metabolism, aging, and longevity, the immune system and DNA repair have been highlighted. A deregulation of the NAD ⁺ levels has been associated with metabolic diseases and aging-related diseases, including neurodegeneration, defective immune responses, and cancer. NAD ⁺ acts as a cofactor through its interplay with NADH, playing an essential role in many enzymatic reactions of energy metabolism, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, and the TCA cycle. NAD ⁺ also plays a role in deacetylation by sirtuins and ADP ribosylation during DNA damage/repair by PARP proteins. Finally, different NAD hydrolase proteins also consume NAD ⁺ while converting it into ADP-ribose or its cyclic counterpart. Some of these proteins, such as CD38, seem to be extensively involved in the immune response. Since NAD cannot be taken directly from food, NAD metabolism is essential, and NAMPT is the key enzyme recovering NAD from nicotinamide and generating most of the NAD cellular pools. Because of the complex network of pathways in which NAD ⁺ is essential, the important role of NAD ⁺ and its key generating enzyme, NAMPT, in cancer is understandable. In the present work, we review the role of NAD ⁺ and NAMPT in the ways that they may influence cancer metabolism, the immune system, stemness, aging, and cancer. Finally, we review some ongoing research on therapeutic approaches.
