Reactive oxygen/nitrogen species contribute substantially to the antileukemia effect of APO866, a NAD lowering agent

Cloux, Anne-Julie; Aubry, Dominique; Heulot, Mathieu; Widmann, Christian; ElMokh, Oussama; Piacente, Francesco; Cea, Michele; Nencioni, Alessio; Bellotti, Axel; Bouzourène, Karima; Pellegrin, Maxime; Mazzolai, Lucia; Duchosal, Michel A.; Nahimana, Aimable

doi:10.18632/oncotarget.27336

Cited by 20 publications

(26 citation statements)

References 59 publications

(66 reference statements)

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“…Although it is not BRCA-deficient, Ewing sarcoma is also characterized by defective HR (96), further supporting the idea that cancers with defective DNA repair mechanisms may have increased susceptibility to NAMPT inhibition. Interestingly, results from a recent study in preclinical leukemia models revealed functional antagonism between NAMPT and PARP inhibitors, suggesting that cell type specific differences in how these pathways interact may be present (97).…”

Section: Dna Damage Repair Responsementioning

confidence: 99%

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Heske

2020

Front. Oncol.

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Tumor cells have increased requirements for NAD +. Thus, many cancers exhibit an increased reliance on NAD + production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD + salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD +-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.

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Section: Dna Damage Repair Responsementioning

confidence: 99%

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Heske

2020

Front. Oncol.

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“…The effect of OT-82 on ROS induction in our models represents an additional example of the differential effects NAMPTis may have on different cell types. Induction of ROS is a known mechanism of NAMPTi-induced killing in a range of cancer cell types [45][46][47][48][49][50] . However, as we demonstrated in this study, induction of ROS was not responsible for OT-82-induced cell death in EWS, suggesting that ROS production is a byproduct of OT-82-induced cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Induction of reactive oxygen species (ROS) is another commonly reported downstream effect of NAMPT inhibition [45][46][47][48][49][50] . While treatment with OT-82 resulted in at least a six-fold increase in ROS in EWS cells, addition of the antioxidant N-acetylcysteine (NAC) did not rescue cellular viability, despite reducing ROS to baseline levels, and suggests that ROS induction is not driving the antiproliferative effects of OT-82 ( Supplementary Fig.…”

Section: Ot-82 Affects Additional Nad + -Dependent Processes In Ews Cmentioning

confidence: 99%

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) with OT-82 induces DNA damage, cell death, and suppression of tumor growth in preclinical models of Ewing sarcoma

et al. 2020

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NAMPT mediates the rate-limiting step of the NAD salvage pathway, which maintains cellular bioenergetics and provides a necessary substrate for functions essential to rapidly proliferating cancer cells. In this study, we evaluated the efficacy and mechanisms of action of OT-82, a novel, high-potency NAMPT inhibitor with a favorable toxicity profile, in preclinical models of Ewing sarcoma (EWS), an aggressive pediatric malignancy with previously reported selective sensitivity to NAMPT inhibition. We show that OT-82 decreased NAD concentration and impaired proliferation of EWS cells in a dose-dependent manner, with IC50 values in the single-digit nanomolar range. Notably, genetic depletion of NAMPT phenocopied pharmacological inhibition. On-target activity of OT-82 was confirmed with the addition of NMN, the product of NAMPT, which rescued NAD concentration and EWS cellular viability. Mechanistically, OT-82 treatment resulted in impaired DNA damage repair through loss of PARP activity, G2 cell-cycle arrest, and apoptosis in EWS cells. Additional consequences of OT-82 treatment included reduction of glycolytic and mitochondrial activity. In vivo, OT-82 impaired tumor growth and prolonged survival in mice bearing EWS xenografts. Importantly, antitumor effect correlated with pharmacodynamic markers of target engagement. Furthermore, combining low-dose OT-82 with low doses of agents augmenting DNA damage demonstrated enhanced antitumor activity in vitro and in vivo. Thus, OT-82 treatment represents a potential novel targeted approach for the clinical treatment of EWS.

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“…And we monitored eleven batches of PNGL samples by the chemical fingerprinting assay [ 31 ]. FK866, as a highly specific NAMPT inhibitor, could inhibit the NAMPT and NAD+ biosynthesis in mammals [ 23 , 36 , 37 ]. Our present experiment has suggested the potential mechanisms in vivo .…”

Section: Methodsmentioning

confidence: 99%

Notoginseng Leaf Triterpenes Ameliorates OGD/R-Induced Neuronal Injury via SIRT1/2/3-Foxo3a-MnSOD/PGC-1α Signaling Pathways Mediated by the NAMPT-NAD Pathway

Xie

Zhu

Zhou

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Cerebral ischemic stroke (CIS) is a common cerebrovascular disease whose main risks include necrosis, apoptosis, and cerebral infarction. But few therapeutic advances and prominent drugs seem to be of value for ischemic stroke in the clinic yet. In the previous study, notoginseng leaf triterpenes (PNGL) from Panax notoginseng stem and leaf have been confirmed to have neuroprotective effects against mitochondrial damages caused by cerebral ischemia in vivo. However, the potential mechanisms of mitochondrial protection have not been fully elaborated yet. Methods. The oxygen and glucose deprivation and reperfusion (OGD/R)-induced SH-SY5Y cells were adopted to explore the neuroprotective effects and the potential mechanisms of PNGL in vitro. Cellular cytotoxicity was measured by MTT, viable mitochondrial staining, and antioxidant marker detection in vitro.Mitochondrial functions were analyzed by ATP content measurement, MMP determination, ROS, NAD, and NADH kit in vitro. And the inhibitor FK866 was adopted to verify the regulation of PNGL on the target NAMPT and its key downstream. Results. In OGD/R models, treatment with PNGL strikingly alleviated ischemia injury, obviously preserved redox balance and excessive oxidative stress, inhibited mitochondrial damage, markedly alleviated energy metabolism dysfunction, improved neuronal mitochondrial functions, obviously reduced neuronal loss and apoptosis in vitro, and thus notedly raised neuronal survival under ischemia and hypoxia. Meanwhile, PNGL markedly increased the expression of nicotinamide phosphoribosyltransferase (NAMPT) in the ischemic regions and OGD/R-induced SH-SY5Y cells and regulated the downstream SIRT1/2-Foxo3a and SIRT1/3-MnSOD/PGC-1α pathways. And FK866 further verified that the protective effects of PNGL might be mediated by the NAMPT in vitro. Conclusions. The mitochondrial protective effects of PNGL are, at least partly, mediated via the NAMPT-NAD+ and its downstream SIRT1/2/3-Foxo3a-MnSOD/PGC-1α signaling pathways. PNGL, as a new drug candidate, has a pivotal role in mitochondrial homeostasis and energy metabolism therapy via NAMPT against OGD-induced SH-SY5Y cell injury.

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Reactive oxygen/nitrogen species contribute substantially to the antileukemia effect of APO866, a NAD lowering agent

Cited by 20 publications

References 59 publications

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) with OT-82 induces DNA damage, cell death, and suppression of tumor growth in preclinical models of Ewing sarcoma

Notoginseng Leaf Triterpenes Ameliorates OGD/R-Induced Neuronal Injury via SIRT1/2/3-Foxo3a-MnSOD/PGC-1α Signaling Pathways Mediated by the NAMPT-NAD Pathway

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