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NAD+ AND cancer

Sailendra Singh, Pallavi Pandey, Sumit Ghosh, Suchitra Banerjee
Andrographolide (AD) is the time-honoured pharmacologically active constituent of the traditionally renowned medicinal plant-Andrographis paniculata. Advancements in the target-oriented drug discovery process have further unravelled the immense therapeutic credibility of another unique molecule-neoandrographolide (NAD). The escalated market demand of these anti-cancer diterpenes is increasingly facing unrelenting hurdles of demand and supply disparity, attributable to their limited yield. Callus and adventitious root cultures were generated to explore their biosynthetic potentials which first time revealed NAD production along with AD...
March 20, 2018: Protoplasma
Masoumeh Nemati, Naser Ajami, Mehrdad Asghari Estiar, Saleheh Rezapour, Reyhaneh Ravanbakhsh Gavgani, Shahryar Hashemzadeh, Hossein Samadi Kafil, Ebrahim Sakhinia
BACKGROUND: To date, 4 classes of histone deacetylases (HDACs) have been identified in humans. Class I HDACs are zinc-dependent and NAD+-independent enzymes, and include 4 isoforms closely related to yeast RPD3: HDAC1, 2, 3, and 8. OBJECTIVES: The aims of the study were to quantitatively evaluate the expression of HDAC3 in colorectal cancer (CRC) and to correlate its expression levels with clinicopathological parameters. MATERIAL AND METHODS: We characterized expression patterns of HDAC3 as class I HDAC isoforms in a cohort of 48 CRC patients by quantitative (real-time) reverse transcription polymerase chain reaction (RT-PCR)...
March 20, 2018: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
Songcheng Yu, Zhen Yan, Feifei Feng, Jing Ni, Wei Wang, Kadijatu Nabie, Yiguo Zhang, Lingbo Qu, Yongjun Wu
Coal tar pitch (CTP) is a key factor in the development of occupational lung cancer. In order to investigate the function of the anti-oxidative signaling pathway regulated by NF-E2-related factor 2 (Nrf2) during cancer development, BEAS-2B cells were cultured with CTP extract for 30 passages. It was revealed that malignant transformation occurred in cells between the 20 and 30th passage. The expression levels of Nrf2 and NAD(P)H:quinone oxidoreductase 1 (NQO1) were promoted throughout the CTP exposure culture, and there was a positive linear correlation between the expression levels of Nrf2 and NQO1...
April 2018: Oncology Letters
Natthakan Thongon, Chiara Zucal, Vito Giuseppe D'Agostino, Toma Tebaldi, Silvia Ravera, Federica Zamporlini, Francesco Piacente, Ruxanda Moschoi, Nadia Raffaelli, Alessandro Quattrone, Alessio Nencioni, Jean-Francois Peyron, Alessandro Provenzani
Background: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods: We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms...
2018: Cancer & Metabolism
Jiangying Kuang, Lei Chen, Qin Tang, Jinhang Zhang, Yanping Li, Jinhan He
Sirt6 is one of the sirtuin family members, a kind of NAD+-dependent histone deacetylase and ADP-ribose transferase enzyme. It has an important role in physiological and pathological processes, regulating aging, cancer, obesity, insulin resistance, inflammation, and energy metabolism. Recent studies have suggested that reduced Sirt6 action is related to obesity and diabetes. Aging and overnutrition, two major risk factors for obesity and diabetes, lead to decreased Sirt6 level and function, which results in abnormal glucose and lipid metabolism...
2018: Frontiers in Physiology
Minna Rahnasto-Rilla, Jonna Tyni, Marjo Huovinen, Elina Jarho, Tomasz Kulikowicz, Sarangan Ravichandran, Vilhelm A Bohr, Luigi Ferrucci, Maija Lahtela-Kakkonen, Ruin Moaddel
Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungus with various pharmacological effects. Due to their plethora of biological activities, they have been studied extensively in drug development. They have been shown to modulate the activity of a NAD+ -dependent histone deacetylase, SIRT6. Because SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer...
March 7, 2018: Scientific Reports
Gaurav Narula, Nirmalaya D Pradhan, Brijesh Arora, Sripad D Banavali
BACKGROUND: Involvement of risk-organs (RO+) in Langerhans cell histiocytosis (LCH) and inadequate early response identifies patients at high risk for relapse and mortality requiring intensive salvage therapy including stem cell transplant, adding cost and toxicity. To mitigate this, we used a standard induction, augmented with metronomic etoposide, and prolonged maintenance-similarly augmented for RO+, and retrospectively analyzed its impact. PROCEDURE: LCH patients from 2009 through 2014 were included...
March 7, 2018: Pediatric Blood & Cancer
Zongdong Li, Natasha M Nesbitt, Lisa E Malone, Dimitri V Gnatenko, Song Wu, Daifeng Wang, Wei Zhu, Geoffrey D Girnun, Wadie F Bahou
Bioenergetic requirements of hematopoietic stem cells (HSC) and pluripotent stem cells (PSC) vary with lineage fate, and cellular adaptations rely largely on substrate (glucose/glutamine) availability and mitochondrial function to balance TCA-derived anabolic and redox-regulated antioxidant functions.  Heme synthesis and degradation converge in a linear pathway that utilizes TCA cycle-derived carbon in cataplerotic reactions of tetrapyrrole biosynthesis, terminated by NAD(P)H-dependent biliverdin reductases (IXα, BLVRA and IXβ, BLVRB) that lead to bilirubin generation and cellular antioxidant functions...
March 2, 2018: Biochemical Journal
Subhadip Hajra, Arup Ranjan Patra, Abhishek Basu, Sudin Bhattacharya
Doxorubicin (DOX) is an anthracycline group of antibiotic available for the treatment of broad spectrum of human cancers. However, patient receiving DOX-therapy, myelosuppression and genotoxicity which may lead to secondary malignancy and dose dependent cardiotoxicity is an imperative adverse effect. Mechanisms behind the DOX-induced toxicities are increased level of oxidative damage, inflammation and apoptosis. Therefore, in search of a potential chemoprotectant, naturally occurring glucosinolate breakdown product Indole-3-Carbinol (I3C) was evaluated against DOX-induced toxicities in Swiss albino mice...
February 26, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Eduardo N Chini, Claudia C S Chini, Jair Machado Espindola Netto, Guilherme C de Oliveira, Wim van Schooten
Recent reports indicate that intracellular NAD levels decline in tissues during chronological aging, and that therapies aimed at increasing cellular NAD levels could have beneficial effects in many age-related diseases. The protein CD38 (cluster of differentiation 38) is a multifunctional enzyme that degrades NAD and modulates cellular NAD homeostasis. At the physiological level, CD38 has been implicated in the regulation of metabolism and in the pathogenesis of multiple conditions including aging, obesity, diabetes, heart disease, asthma, and inflammation...
February 23, 2018: Trends in Pharmacological Sciences
Daniela Buonvicino, Francesca Mazzola, Federica Zamporlini, Francesco Resta, Giuseppe Ranieri, Emidio Camaioni, Mirko Muzzi, Riccardo Zecchi, Giuseppe Pieraccini, Christian Dölle, Massimo Calamante, Gianluca Bartolucci, Mathias Ziegler, Barbara Stecca, Nadia Raffaelli, Alberto Chiarugi
Interest in the modulation of nicotinamide adenine dinucleotide (NAD) metabolome is gaining great momentum because of its therapeutic potential in different human disorders. Suppression of nicotinamide salvage by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, however, gave inconclusive results in neoplastic patients because several metabolic routes circumvent the enzymatic block converging directly on nicotinamide mononucleotide adenylyl transferases (NMNATs) for NAD synthesis. Unfortunately, NMNAT inhibitors have not been identified...
February 19, 2018: Cell Chemical Biology
James B Kirkland, Mirella L Meyer-Ficca
Nicotinic acid and nicotinamide, collectively referred to as niacin, are nutritional precursors of the bioactive molecules nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP are important cofactors for most cellular redox reactions, and as such are essential to maintain cellular metabolism and respiration. NAD also serves as a cosubstrate for a large number of ADP-ribosylation enzymes with varied functions. Among the NAD-consuming enzymes identified to date are important genetic and epigenetic regulators, e...
2018: Advances in Food and Nutrition Research
Agnes L C Ong, Thamil Selvee Ramasamy
Regulatory role of Sirtuin 1 (SIRT1), one of the most extensively studied members of its kind in histone deacetylase family in governing multiple cellular fates, is predominantly linked to p53 activity. SIRT1 deacetylates p53 in a NAD+-dependent manner to inhibit transcription activity of p53, in turn modulate pathways that are implicated in regulation of tissue homoeostasis and many disease states. In this review, we discuss the role of SIRT1-p53 pathway and its regulatory axis in the cellular events which are implicated in cellular aging, cancer and reprogramming...
February 21, 2018: Ageing Research Reviews
Karina N Gonzalez Herrera, Elma Zaganjor, Yoshinori Ishikawa, Jessica B Spinelli, Haejin Yoon, Jia-Ren Lin, F Kyle Satterstrom, Alison Ringel, Stacy Mulei, Amanda Souza, Joshua M Gorham, Craig C Benson, Jonathan G Seidman, Peter K Sorger, Clary B Clish, Marcia C Haigis
Sirtuin 3 (SIRT3) is a NAD+ -dependent deacetylase downregulated in aging and age-associated diseases such as cancer and neurodegeneration and in high-fat diet (HFD)-induced metabolic disorders. Here, we performed a small-molecule screen and identified an unexpected metabolic vulnerability associated with SIRT3 loss. Azaserine, a glutamine analog, was the top compound that inhibited growth and proliferation of cells lacking SIRT3. Using stable isotope tracing of glutamine, we observed its increased incorporation into de novo nucleotide synthesis in SIRT3 knockout (KO) cells...
February 20, 2018: Cell Reports
Anusha Jayaraman, Praveen Kumar, Silvia Marin, Pedro de Atauri, Francesca Mateo, Timothy M Thomson, Josep J Centelles, Stewart F Graham, Marta Cascante
Tumour angiogenesis is an important hallmark of cancer and the study of its metabolic adaptations, downstream to any cellular change, can reveal attractive targets for inhibiting cancer growth. In the tumour microenvironment, endothelial cells (ECs) interact with heterogeneous tumour cell types that drive angiogenesis and metastasis. In this study we aim to characterize the metabolic alterations in ECs influenced by the presence of tumour cells with extreme metastatic abilities. Human umbilical vein endothelial cells (HUVECs) were subjected to different microenvironmental conditions, such as the presence of highly metastatic PC-3M and highly invasive PC-3S prostate cancer cell lines, in addition to the angiogenic activator vascular endothelial growth factor (VEGF), under normoxia...
2018: PloS One
Mehdi Touat, Tony Sourisseau, Nicolas Dorvault, Roman M Chabanon, Marlène Garrido, Daphné Morel, Dragomir B Krastev, Ludovic Bigot, Julien Adam, Jessica Frankum, Sylvère Durand, Clement Pontoizeau, Sylvie Souquère, Mei-Shiue Kuo, Sylvie Sauvaigo, Faraz Mardakheh, Alain Sarasin, Ken A Olaussen, Luc Friboulet, Frédéric Bouillaud, Gérard Pierron, Alan Ashworth, Anne Lombès, Christopher J Lord, Jean-Charles Soria, Sophie Postel-Vinay
Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. ERCC1 deficiency is frequently found in non-small cell lung cancers, making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in this disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT)...
February 15, 2018: Journal of Clinical Investigation
Seyoung Lee, Dong Jun Park, Jihee Yoon, Seung Hyuck Bang, Yang-Hoon Kim, Jiho Min
Formaldehyde is a toxic compound due to its ability to react with proteins, nucleic acids and lipids and is the primary cause of nasopharyngeal cancer and sick building syndrome (SBS). Aldehyde dehydrogenases (ALDHs) are able to oxidize aldehyde substrates and maintain cellular homeostasis by metabolic reactions in prokaryotic and eukaryotic cells. ALDHs catalyze the conversions of various aldehydes to carboxylic acids using NAD or NADP as a cofactor. In this study, we designed a method for using aldehyde dehydrogenase 6 (ALD6) from recombinant Saccharomyces cerevisiae to reduce formaldehyde...
April 1, 2018: Journal of Nanoscience and Nanotechnology
Nobuyuki Arakawa, Ayaka Okubo, Shinji Yasuhira, Kazuhiro Takahashi, Hiroo Amano, Toshihide Akasaka, Tomoyuki Masuda, Masahiko Shibazaki, Chihaya Maesawa
NAD(P)H quinone oxidoreductase 1 (NQO1)-dependent antitumor drugs such as β-lapachone (β-lap) are attractive candidates for cancer chemotherapy because several tumors exhibit higher expression of NQO1 than adjacent tissues. Although the association between NQO1 and β-lap has been elucidated, the effects of a NQO1-inducer and β-lap used in combination remain to be clarified. It has previously been reported that melanoma cell lines have detectable levels of NQO1 expression and are sensitive to NQO1-dependent drugs such as 17-allylamino-17-demethoxygeldanamycin...
February 2018: Oncology Letters
Na-Young Song, Yeon-Hwa Lee, Hye-Kyung Na, Jeong-Heum Baek, Young-Joon Surh
Leptin, a representative adipokine secreted from the white adipose tissue, is considered as a potential linker between obesity and cancer. SIRT1 is a NAD+-dependent histone/protein deacetylase speculated to function as an oncogene. In the present study, we found that leptin signaling-defective ob/ob and db/db mice had lower colonic expression of SIRT1 compared with leptin signaling-intact C57BL/6J mice, implying that leptin signaling is crucial for SIRT1 expression in vivo. Moreover, leptin induced up-regulation of SIRT1 in human colon cancer (HCT-116) cells...
February 7, 2018: Biochemical Pharmacology
Hai Wang, Zan Gao, Xuanyou Liu, Pranay Agarwal, Shuting Zhao, Daniel W Conroy, Guang Ji, Jianhua Yu, Christopher P Jaroniec, Zhenguo Liu, Xiongbin Lu, Xiaodong Li, Xiaoming He
Multidrug resistance is a major challenge to cancer chemotherapy. The multidrug resistance phenotype is associated with the overexpression of the adenosine triphosphate (ATP)-driven transmembrane efflux pumps in cancer cells. Here, we report a lipid membrane-coated silica-carbon (LSC) hybrid nanoparticle that targets mitochondria through pyruvate, to specifically produce reactive oxygen species (ROS) in mitochondria under near-infrared (NIR) laser irradiation. The ROS can oxidize the NADH into NAD+ to reduce the amount of ATP available for the efflux pumps...
February 8, 2018: Nature Communications
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