Divergent metabolic responses dictate vulnerability to NAMPT inhibition in ovarian cancer

Kudo, Kohsuke; Nomura, Miyuki; Sakamoto, Yohei; Ito, Shigemi; Morita, Mami; Kawai, Masaaki; Yamashita, Yoshihisa; Itō, Kiyoshi; Yamada, Hidekazu; Shima, Hiroshi; Yaegashi, Nobuo; Tanuma, Nobuhiro

doi:10.1002/1873-3468.13736

Cited by 12 publications

(12 citation statements)

References 26 publications

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“…Piacente et al demonstrated that NAPRT-proficient ovarian and pancreatic cancers are resistant to FK866, whereas NAPRT downregulation through gene silencing or chemical inhibition with 2-hydroxynicotinic acid (2-HNA) sensitized tumor cells to NAMPT inhibitors both in vitro and in vivo [25]. In line with these results, another study highlighted that sensitivity to NAMPT inhibition in several ovar-ian cancer cell lines was inversely proportional to NAPRT expression [41]. Despite its usefulness in basic research as NAPRTi, the low molecular weight and high functionality of 2-hydroxynicotinic acid suggest that this compound could have non-specific effects.…”

Section: Introductionmentioning

confidence: 91%

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: 91%

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

et al. 2022

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confidence: 99%

“…[7][8][9][10][11] Intriguingly, some cancer-type-specific metabolic activities show narrow requirements for a particular nutrient, which represents a unique vulnerability of that cancer to therapeutic targeting based on that nutrient. [12][13][14] It is clear that both tumor and non-tumor cells are influenced by the availability of nutrients in their microenvironment 15 (Figure 2). In vivo, the concentrations of many circulating nutrients, which are synthesized de novo or absorbed due to dietary intake, are regulated systemically, although concentrations of some nutrients in the tumor interstitial fluid reportedly differ from those seem in plasma.…”

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confidence: 99%

Dietary intervention as a therapeutic for cancer

et al. 2020

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Cancer metabolism is influenced by availability of nutrients in the microenvironment and can to some extent be manipulated by dietary modifications that target oncogenic metabolism. As yet, few dietary interventions have been scientifically proven to mitigate disease progression or enhance any other kind of therapy in human cancer. However, recent advances in the understanding of cancer metabolism enable us to predict or devise effective dietary interventions that might antagonize tumor growth. In fact, evidence emerging from preclinical models suggests that appropriate combinations of specific cancer therapies with dietary interventions could critically impact therapeutic efficacy. Here, we review the potential benefits of precision nutrition approaches in augmenting the efficacy of cancer treatment.

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“…The rate-limiting enzyme of this pathway, NAMPT, has been targeted in pre-clinical studies and in clinical trials for treatment of multiple cancers, with mixed results 29 , 30 . Recent studies using NAMPT inhibitors as monotherapy in ovarian cancer cell lines have shown promising results to overcome drug resistance in certain contexts 31 , 32 . We evaluated the inhibition of NAMPT using the small molecule daporinad 33 in four of our acquired resistance models (those with higher IC 50 values to olaparib) and observed little to no effect.…”

Section: Resultsmentioning

confidence: 99%

“…3 a). On the other hand, the inhibition of NAMPT prevents cancer cells from regenerating NAD+ from nicotinamide, thus drastically reducing the intracellular concentration of this coenzyme 32 . We confirmed that this is the case by quantifying NAD+ in OV1946or cells after 24 h of treatment and show that the relative NAD+ levels in daporinad-treated cells are significantly lower than in untreated controls.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of nicotinamide dinucleotide salvage pathway counters acquired and intrinsic poly(ADP-ribose) polymerase inhibitor resistance in high-grade serous ovarian cancer

Sauriol

Carmona

Udaskin

et al. 2023

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Epithelial ovarian cancer is the most lethal gynecological malignancy, owing notably to its high rate of therapy-resistant recurrence in spite of good initial response to chemotherapy. Although poly(ADP-ribose) polymerase inhibitors (PARPi) have shown promise for ovarian cancer treatment, extended therapy usually leads to acquired PARPi resistance. Here we explored a novel therapeutic option to counter this phenomenon, combining PARPi and inhibitors of nicotinamide phosphoribosyltransferase (NAMPT). Cell-based models of acquired PARPi resistance were created through an in vitro selection procedure. Using resistant cells, xenograft tumors were grown in immunodeficient mice, while organoid models were generated from primary patient tumor samples. Intrinsically PARPi-resistant cell lines were also selected for analysis. Our results show that treatment with NAMPT inhibitors effectively sensitized all in vitro models to PARPi. Adding nicotinamide mononucleotide, the resulting NAMPT metabolite, abrogated the therapy-induced cell growth inhibition, demonstrating the specificity of the synergy. Treatment with olaparib (PARPi) and daporinad (NAMPT inhibitor) depleted intracellular NAD+ , induced double-strand DNA breaks, and promoted apoptosis as monitored by caspase-3 cleavage. The two drugs were also synergistic in mouse xenograft models and clinically relevant patient-derived organoids. Therefore, in the context of PARPi resistance, NAMPT inhibition could offer a promising new option for ovarian cancer patients.

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Divergent metabolic responses dictate vulnerability to NAMPT inhibition in ovarian cancer

Abstract: This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record.

Cited by 12 publications

References 26 publications

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

Dietary intervention as a therapeutic for cancer

Inhibition of nicotinamide dinucleotide salvage pathway counters acquired and intrinsic poly(ADP-ribose) polymerase inhibitor resistance in high-grade serous ovarian cancer

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