The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies

Nahimana, Aimable; Attinger, Antoine; Aubry, Dominique; Greaney, Peter; Ireson, Christopher R.; Thougaard, Annemette; Tjørnelund, Jette; Dawson, Keith M.; Dupuis, Marc; Duchosal, Michel A.

doi:10.1182/blood-2008-08-173369

Cited by 169 publications

(206 citation statements)

References 23 publications

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“…Experimental in vitro and in vivo data provides support to this notion [10,12,13]. Furthermore, since NAD is involved in DNA repair processes, NAD depletion would be an interesting principle for combinations, especially with DNA damaging drugs or radiotherapy [8,14,17].…”

Section: Discussionmentioning

confidence: 99%

“…Since tumour cells have increased PARP activation, high ATP demands and inefficient ATP production through the Warburg effect, tumour cells would be expected to be more sensitive than normal cells to inhibition of NAD synthesis [5]. Thus, NAD synthesis inhibitors could provide an advantageous therapeutic ratio as cancer drugs, as supported by preclinical data [5,[10][11][12][13].…”

Section: Introductionmentioning

confidence: 98%

“…NAD is an important co-factor in the oxidative phosphorylation chain as well as a substrate for enzymes involved in genomic stability, apoptosis, cell signalling, stress tolerance and metabolism [5][6][7]. NAD depletion will lead to, eg lowered ATP levels and inhibition of poly(ADP-ribose) polymerases (PARPs) that are involved in DNA repair [5,[8][9][10]. Since tumour cells have increased PARP activation, high ATP demands and inefficient ATP production through the Warburg effect, tumour cells would be expected to be more sensitive than normal cells to inhibition of NAD synthesis [5].…”

Section: Introductionmentioning

confidence: 99%

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Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Heideman

Berglund

Larsson

et al. 2009

Cancer Chemother Pharmacol

160

150

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2 AbstractPurpose Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials. Conclusions Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low. Methods

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Heideman

Berglund

Larsson

et al. 2009

Cancer Chemother Pharmacol

160

150

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“…The recently developed small molecule inhibitor APO866 has been shown to act as a competitive inhibitor of PBEF/NAMPT activity by inhibiting binding of its natural substrate, nicotinamide (14,15). Moreover, in vivo, APO866 displays antiinflammatory effects, and favorable results have been obtained with APO866 treatment in murine tumor models and models of inflammation (16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

Evans

Williams

Hayes

et al. 2011

Arthritis & Rheumatism

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Objective. To assess the ability of pre-B cell colony-enhancing factor (PBEF) to regulate inflammation and degradative processes in inflammatory arthritis, using the small molecule inhibitor APO866 in human fibroblasts in vitro and in murine collageninduced arthritis (CIA).Methods. Enzyme-linked immunosorbent assays were used to examine regulation of expression of metalloproteinases and chemokines in human fibroblasts. The role of PBEF was further examined using APO866 in mice with CIA, with effects on disease activity assessed using radiography, histology, in vivo imaging, and quantitative polymerase chain reaction (qPCR).Results. In vitro activation of human fibroblasts with PBEF promoted expression of matrix metalloproteinase 3 (MMP-3), CCL2, and CXCL8, an effect inhibited by APO866. In mice with CIA, early intervention with APO866 inhibited synovial inflammation, including chemokine-directed leukocyte infiltration, and reduced a systemic marker of inflammation, serum hyaluronic acid. APO866 blockade led to reduced expression of MMP-3 and MMP-13 in joint extracts and to a reduction in a systemic marker of cartilage erosion, serum cartilage oligomeric matrix protein. Radiologic images revealed that APO866 protected against bone erosion, while qPCR demonstrated inhibition of RANKL expression. In mice with established disease, APO866 reduced synovial inflammation and cartilage destruction, and halted bone erosion. In addition, APO866 reduced the activity of MMP-3, CCL2, and RANKL in vivo, and inhibited production of CCL2 and RANKL in synovial explants from arthritic mice, a result that was reversed with nicotinamide mononucleotide.Conclusion. These findings confirm PBEF to be an important regulator of inflammation, cartilage catabolism, and bone erosion, and highlight APO866 as a promising therapeutic agent for targeting PBEF activity in inflammatory arthritis.Pre-B cell colony-enhancing factor (PBEF) represents an inflammatory mediator that exerts enzymatic activities and is highly expressed within the synovial tissue and plasma of patients with rheumatoid arthritis (1,2). In this respect, PBEF acts as a nicotinamide phosphoribosyltransferase (referred to as NAMPT) that controls NAD biosynthesis by catalyzing nicotinamide with 5-phosphoribosyl-1-pyrophosphate (3-5). Conversely, exogenous PBEF is also described as an adipocytokine (referred to as visfatin), and can regulate cellular processes via activation of transcriptional events through NF-B, phosphatidylinositol 3-kinase, and MAP kinase (6-8). Several groups have shown that PBEF interacts with the insulin receptor (8-10); however, this notion remains controversial (11,12), and it may be that PBEF signals through an alternative signaling route. It is also unlikely that this signaling effect is attributable to the endotoxin that may be present in PBEF preparations, since coincubation with polymixin B shows no abrogation of PBEF signaling (6,10,13).In vitro activation of signaling pathways by PBEF has been shown to regulate the expression of metalloproteinases...

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“…Starting from the early 2000s, Nampt inhibitors such as FK866 [2] have become available, rapidly proving to be valuable tools to study the effects of NAD + depletion in several disease models. As a result, Nampt inhibitors as monotherapy have demonstrated potent antitumor activity in preclinical cancer models [3][4][5][6][7]. In such a scenario, investigators have also tested NAD + -depleting agents in combination with antineoplastic agents, chemotherapy, or radiotherapy in a wide range of hematological malignancies, including AML, MM, and lymphomas, observing an increased activity and overall tolerability of these agents [8][9][10][11][12].…”

mentioning

confidence: 99%

Exploiting tumor vulnerabilities: NAD⁺-depleting agents combined with anti-tumor drugs as innovative strategy to treat hematological malignancies

Cea

Soncini

Gobbi

et al. 2016

Expert Review of Anticancer Therapy

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The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies

Cited by 169 publications

References 23 publications

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

Exploiting tumor vulnerabilities: NAD⁺-depleting agents combined with anti-tumor drugs as innovative strategy to treat hematological malignancies

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The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies

Cited by 169 publications

References 23 publications

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

Exploiting tumor vulnerabilities: NAD+-depleting agents combined with anti-tumor drugs as innovative strategy to treat hematological malignancies

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Exploiting tumor vulnerabilities: NAD⁺-depleting agents combined with anti-tumor drugs as innovative strategy to treat hematological malignancies