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NAD+ AND cancer

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https://www.readbyqxmd.com/read/28087461/low-glucose-stress-decreases-cellular-nadh-and-mitochondrial-atp-in-colonic-epithelial-cancer-cells-influence-of-mitochondrial-substrates
#1
Magdalena L Circu, Ronald E Maloney, Tak Yee Aw
In this study, we investigated how colonic epithelial cells maintained pyridine nucleotide (NADH/NAD(+)) redox homeostasis upon acute metabolic variation imposed by glucose deprivation or supplementation with mitochondrial substrates, succinate and malate/glutamate (M/G). Our results showed that low glucose caused cellular NADH/NAD(+) redox imbalance that diminished lactate dehydrogenase (LDH) activity and resulted in lower lactate contents. The concurrent activation of malic enzyme (ME) suggested a role for malate in preserving cellular pyruvate that remained unchanged at low glucose...
January 10, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28073696/spop-promotes-sirt2-degradation-and-suppresses-non-small-cell-lung-cancer-cell-growth
#2
Jie Luo, Yu-Chen Bao, Xian-Xiu Ji, Bin Chen, Qin-Fang Deng, Song-Wen Zhou
SIRT2 is a NAD-dependent deacetylase and inhibition of SIRT2 has a broad anticancer activity. Here we report that SPOP binds to SIRT2 and mediates its degradation by the 26S proteasome, which can be blocked by MG132 treatment. We also found that the levels of SPOP significantly decreased, while the levels of SIRT2 significantly increased in non-small cell lung cancer (NSCLC) cell lines, compared to normal bronchial epithelial cell line and NSCLC specimens, compared to the paired non-tumor lung tissue. Furthermore, SPOP can suppress NSCLC cell growth...
January 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28073422/-research-advances-in-the-association-between-deacetylase-sirtuin3-and-liver-diseases
#3
J Yu, C Chen, W X Wang
The deacetylase Sirtuin 3 (SIRT3) is a member of the Sirtuins mainly located in the mitochondrial matrix, and as a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, it can regulate cellular energy metabolism and oxidative stress-related pathways. The liver is the largest solid organ in the human body and plays a very important role in substance metabolism. Based on the features of SIRT3, it is closely associated with the development and progression of certain liver diseases. This article reviews the research advances in the role of SIRT3 in non-alcoholic fatty liver disease, liver cancer, and hepatic ischemia-reperfusion injury...
December 20, 2016: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
https://www.readbyqxmd.com/read/28069826/endostatin-inhibits-androgen-independent-prostate-cancer-growth-by-suppressing-nuclear-receptor-mediated-oxidative-stress
#4
Joo Hyoung Lee, Minsung Kang, Hong Wang, Gurudatta Naik, James A Mobley, Guru Sonpavde, W Timothy Garvey, Victor M Darley-Usmar, Selvarangan Ponnazhagan
Androgen-deprivation therapy has been identified to induce oxidative stress in prostate cancer (PCa), leading to reactivation of androgen receptor (AR) signaling in a hormone-refractory manner. Thus, antioxidant therapies have gained attention as adjuvants for castration-resistant PCa. Here, we report for the first time that human endostatin (ES) prevents androgen-independent growth phenotype in PCa cells through its molecular targeting of AR and glucocorticoid receptor (GR) and downstream pro-oxidant signaling...
January 9, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28063999/relationship-between-intracellular-ph-metabolic-co-factors-and-caspase-3-activation-in-cancer-cells-during-apoptosis
#5
Tatiana F Sergeeva, Marina V Shirmanova, Olga A Zlobovskaya, Alena I Gavrina, Varvara V Dudenkova, Maria M Lukina, Konstantin A Lukyanov, Elena V Zagaynova
A complex cascade of molecular events occurs in apoptotic cells but cell-to-cell variability significantly complicates determination of the order and interconnections between different processes. For better understanding of the mechanisms of programmed cell death, dynamic simultaneous registration of several parameters is required. In this paper we used multiparameter fluorescence microscopy to analyze energy metabolism, intracellular pH and caspase-3 activation in living cancer cells in vitro during staurosporine-induced apoptosis...
January 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28052592/innocent-but-deadly-non-toxic-organoiridium-catalysts-promote-selective-cancer-cell-death
#6
Lu Yang, Sohini Bose, Anh H Ngo, Loi Hung Do
We demonstrate that non-toxic organoiridum complexes can selectively chemosensitize cancer cells toward platinum anti-proliferative agents. Treatment of human cancer cells (breast, colon, eye/retina, head/neck, lung, ovary, and blood) with the iridium chemosensitizers led to the lowering of the Pt drug carboplatin's 50% growth inhibition concentration (IC50) by up to about 30-50%. Interestingly, non-cancer cells were mostly resistant to the chemosensitizing effects of the iridium complexes. Cell culture studies indicate that cancer cells that were administered with Ir show significantly higher reactive oxygen species concentrations as well as NAD+/NADH ratios (oxidized vs...
January 4, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28052347/apoptotic-effects-of-bovine-apo-lactoferrin-on-hela-tumor-cells
#7
Carla Luzi, Fabrizia Brisdelli, Roberto Iorio, Argante Bozzi, Veronica Carnicelli, Antonio Di Giulio, Anna Rita Lizzi
Lactoferrin (Lf), a cationic iron-binding glycoprotein of 80 kDa present in body secretions, is known as a compound with marked antimicrobial activity. In the present study, the apoptotic effect of iron-free bovine lactoferrin (apo-bLf) on human epithelial cancer (HeLa) cells was examined in association with reactive oxygen species and glutathione (GSH) levels. Apoptotic effect of iron-free bovine lactoferrin inhibited the growth of HeLa cells after 48 hours of treatment while the diferric-bLf was ineffective in the concentration range tested (from 1 to 12...
January 3, 2017: Cell Biochemistry and Function
https://www.readbyqxmd.com/read/28042046/rational-design-of-selective-allosteric-inhibitors-of-phgdh-and-serine-synthesis-with-anti-tumor-activity
#8
Qian Wang, Maria V Liberti, Pei Liu, Xiaobing Deng, Ying Liu, Jason W Locasale, Luhua Lai
Metabolic reprogramming in cancer cells facilitates growth and proliferation. Increased activity of the serine biosynthetic pathway through the enzyme phosphoglycerate dehydrogenase (PHGDH) contributes to tumorigenesis. With a small substrate and a weak binding cofactor, (NAD(+)), inhibitor development for PHGDH remains challenging. Instead of targeting the PHGDH active site, we computationally identified two potential allosteric sites and virtually screened compounds that can bind to these sites. With subsequent characterization, we successfully identified PHGDH non-NAD(+)-competing allosteric inhibitors that attenuate its enzyme activity, selectively inhibit de novo serine synthesis in cancer cells, and reduce tumor growth in vivo...
December 20, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/28006669/alkynyloxy-derivatives-of-5-8-quinolinedione-synthesis-in%C3%A2-vitro-cytotoxicity-studies-and-computational-molecular-modeling-with-nad-p-h-quinone-oxidoreductase-1
#9
Monika Kadela-Tomanek, Maria Jastrzębska, Bartosz Pawełczak, Ewa Bębenek, Elwira Chrobak, Małgorzata Latocha, Maria Książek, Joachim Kusz, Stanisław Boryczka
The natural 7-amino-5,8-quinolinodione antibiotics were the substrate for the NQO1 protein. The structure-activity relationship showed that the 5,8-quinolinedione moiety was responsible for the interaction with the enzyme. In our research, we presented the synthesis, cytotoxic activity and theoretical study of a 5,8-quinolinedione compound as a potential inhibitor of the NQO1 enzyme. Mono and disubstituted alkynyloxy derivatives of the 5,8-quinolinedione were synthesized and characterized by (1)H, (13)C NMR, IR and HR-MS spectra...
December 15, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28000977/silac-based-quantitative-proteomic-analysis-reveals-widespread-molecular-alterations-in-human-skin-keratinocytes-upon-chronic-arsenic-exposure
#10
Sartaj Ahmad Mir, Sneha M Pinto, Somnath Paul, Remya Raja, Vishalakshi Nanjappa, Nazia Syed, Jayshree Advani, Santosh Renuse, Nandini A Sahasrabuddhe, T S Keshava Prasad, Ashok K Giri, Harsha Gowda, Aditi Chatterjee
Chronic exposure to arsenic is associated with dermatological and nondermatological disorders. Consumption of arsenic-contaminated drinking water results in accumulation of arsenic in liver, spleen, kidneys, lungs, and gastrointestinal tract. Although arsenic is cleared from these sites, a substantial amount of residual arsenic is left in keratin-rich tissues including skin. Epidemiological studies suggest the association of skin cancer upon arsenic exposure, however, the mechanism of arsenic-induced carcinogenesis is not completely understood...
October 19, 2016: Proteomics
https://www.readbyqxmd.com/read/27994519/anticancer-effects-of-a-new-sirt-inhibitor-mhy2256-against-human-breast-cancer-mcf-7-cells-via-regulation-of-mdm2-p53-binding
#11
Eun Young Park, Youngwoo Woo, Seong Jin Kim, Do Hyun Kim, Eui Kyung Lee, Umasankar De, Kyeong Seok Kim, Jaewon Lee, Jee H Jung, Ki-Tae Ha, Wahn Soo Choi, In Su Kim, Byung Mu Lee, Sungpil Yoon, Hyung Ryong Moon, Hyung Sik Kim
The sirtuins (SIRTs), a family of NAD(+)-dependent class III histone deacetylase, are involved in various biological processes including cell survival, division, senescence, and metabolism via activation of the stress-response pathway. Recently, inhibition of SIRTs has been considered a promising anticancer strategy, but their precise mechanisms of action are not well understood. In particular, the relevance of p53 to SIRT-induced effects has not been fully elucidated. We investigated the anticancer effects of a novel SIRT inhibitor, MHY2256, and its efficacy was compared to that of salermide in MCF-7 (wild-type p53) and SKOV-3 (null-type p53) cells...
2016: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/27986568/distinct-responses-of-compartmentalized-glutathione-redox-potentials-to-pharmacologic-quinones-targeting-nqo1
#12
Vladimir L Kolossov, Nagendraprabhu Ponnuraj, Jessica N Beaudoin, Matthew T Leslie, Paul J Kenis, H Rex Gaskins
Deoxynyboquinone (DNQ), a potent novel quinone-based antineoplastic agent, selectively kills solid cancers with overexpressed cytosolic NAD(P)H:quinone oxidoreductase-1 (NQO1) via excessive ROS production. A genetically encoded redox-sensitive probe was used to monitor intraorganellar glutathione redox potentials (EGSH) as a direct indicator of cellular oxidative stress following chemotherapeutic administration. Beta-lapachone (β-lap) and DNQ-induced spatiotemporal redox responses were monitored in human lung A549 and pancreatic MIA-PaCa-2 adenocarcinoma cells incubated with or without dicumarol and ES936, potent NQO1 inhibitors...
December 14, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27984176/parp-inhibition-protects-against-alcoholic-and-nonalcoholic-steatohepatitis
#13
Partha Mukhopadhyay, Béla Horváth, Mohanraj Rajesh, Zoltán V Varga, Karim Gariani, Dongryeol Ryu, Zongxian Cao, Eileen Holovac, Ogyi Park, Zhou Zhou, Ming-Jiang Xu, Wei Wang, Grzegorz Godlewski, Janos Paloczi, Balazs Tamas Nemeth, Yuri Persidsky, Lucas Liaudet, György Haskó, Peter Bai, A Hamid Boulares, Johan Auwerx, Bin Gao, Pal Pacher
BACKGROUND & AIMS: Mitochondrial dysfunction, oxidative stress, inflammation, and metabolic reprograming are crucial contributors of hepatic injury and subsequent development of liver fibrosis. Poly(ADP-ribose) polymerases (PARP) and their interplay with sirtuins have an important role in the regulation of intermediary metabolism, however, if PARP inhibition is capable to affect alcoholic and nonalcoholic steatohepatitis (ASH/NASH) has not been much studied. METHODS: We investigated the effects of genetic deletion of PARP1 and pharmacological inhibition of PARP with structurally different inhibitors in models of early alcoholic steatohepatitis, as well as on Kupffer cell activation in vitro by using biochemical assays, real-time PCR, and histology analyses...
October 28, 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/27975234/pharmacokinetics-and-derivation-of-an-anticancer-dosing-regimen-for-the-novel-anti-cancer-agent-isobutyl-deoxynyboquinone-ib-dnq-a-nqo1-bioactivatable-molecule-in-the-domestic-felid-species
#14
Alycen P Lundberg, Joshua M Francis, Malgorzata Pajak, Elizabeth I Parkinson, Kathryn L Wycislo, Thomas J Rosol, Megan E Brown, Cheryl A London, Levent Dirikolu, Paul J Hergenrother, Timothy M Fan
Isobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB-DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable anticancer agent...
December 14, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27973747/quinolinic-acid-induces-neuritogenesis-in-sh-sy5y-neuroblastoma-cells-independently-of-nmda-receptor-activation
#15
Juan-Manuel Hernandez-Martinez, Caroline M Forrest, L Gail Darlington, Robert A Smith, Trevor W Stone
Glutamate and nicotinamide adenine dinucleotide (NAD+) have been implicated in neuronal development and several types of cancer. The kynurenine pathway of tryptophan metabolism includes quinolinic acid (QA) which is both a selective agonist at N-methyl-D-aspartate (NMDA) receptors and also a precursor for the formation of NAD+. The effect of QA on cell survival and differentiation has therefore been examined on SH-SY5Y human neuroblastoma cells. Retinoic acid (RA, 10 μM) induced differentiation of SH-SY5Y cells into a neuronal phenotype showing neurite growth...
December 14, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27960087/leveraging-an-nqo1-bioactivatable-drug-for-tumor-selective-use-of-poly-adp-ribose-polymerase-inhibitors
#16
Xiumei Huang, Edward A Motea, Zachary R Moore, Jun Yao, Ying Dong, Gaurab Chakrabarti, Jessica A Kilgore, Molly A Silvers, Praveen L Patidar, Agnieszka Cholka, Farjana Fattah, Yoonjeong Cha, Glenda G Anderson, Rebecca Kusko, Michael Peyton, Jingsheng Yan, Xian-Jin Xie, Venetia Sarode, Noelle S Williams, John D Minna, Muhammad Beg, David E Gerber, Erik A Bey, David A Boothman
Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1(+) cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone...
December 12, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27959364/an-efficient-two-photon-fluorescent-probe-for-human-nad-p-h-quinone-oxidoreductase-hnqo1-detection-and-imaging-in-tumor-cells
#17
Nahyun Kwon, Myoung Ki Cho, Sang Jun Park, Dayoung Kim, Sang-Jip Nam, Lei Cui, Hwan Myung Kim, Juyoung Yoon
A new quinone propionic acid locked TP fluorophore which can be used for human NAD(P)H:quinone oxidoreductase (hNQO1) detection was developed. The probe, TPQ, which displays high selectivity and anti-interference ability, was successfully applied to endogenous hNQO1 imaging and for the identification of different cancer cells.
January 3, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/27930300/an-nad-dependent-transcriptional-program-governs-self-renewal-and-radiation-resistance-in-glioblastoma
#18
Amit D Gujar, Son Le, Diane D Mao, David Y A Dadey, Alice Turski, Yo Sasaki, Diane Aum, Jingqin Luo, Sonika Dahiya, Liya Yuan, Keith M Rich, Jeffrey Milbrandt, Dennis E Hallahan, Hiroko Yano, David D Tran, Albert H Kim
Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD(+)). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD(+) synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival...
December 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27929731/autophagic-homeostasis-is-required-for-the-pluripotency-of-cancer-stem-cells
#19
Tanveer Sharif, Emma Martell, Cathleen Dai, Barry E Kennedy, Patrick Murphy, Derek R Clements, Youra Kim, Patrick W K Lee, Shashi A Gujar
Pluripotency is an important feature of cancer stem cells (CSCs) that contributes to self-renewal and chemoresistance. The maintenance of pluripotency of CSCs under various pathophysiological conditions requires a complex interaction between various cellular pathways including those involved in homeostasis and energy metabolism. However, the exact mechanisms that maintain the CSC pluripotency remain poorly understood. In this report, using both human and murine models of CSCs, we demonstrate that basal levels of autophagy are required to maintain the pluripotency of CSCs, and that this process is differentially regulated by the rate-limiting enzyme in the NAD(+) synthesis pathway NAMPT (nicotinamide phosphoribosyltransferase) and the transcription factor POU5F1/OCT4 (POU class 5 homeobox 1)...
December 8, 2016: Autophagy
https://www.readbyqxmd.com/read/27911769/reductive-carboxylation-is-a-major-metabolic-pathway-in-the-retinal-pigment-epithelium
#20
Jianhai Du, Aya Yanagida, Kaitlen Knight, Abbi L Engel, Anh Huan Vo, Connor Jankowski, Martin Sadilek, Van Thi Bao Tran, Megan A Manson, Aravind Ramakrishnan, James B Hurley, Jennifer R Chao
The retinal pigment epithelium (RPE) is a monolayer of pigmented cells that requires an active metabolism to maintain outer retinal homeostasis and compensate for oxidative stress. Using (13)C metabolic flux analysis in human RPE cells, we found that RPE has an exceptionally high capacity for reductive carboxylation, a metabolic pathway that has recently garnered significant interest because of its role in cancer cell survival. The capacity for reductive carboxylation in RPE exceeds that of all other cells tested, including retina, neural tissue, glial cells, and a cancer cell line...
December 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
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