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NQO1 AND Lapachone

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https://www.readbyqxmd.com/read/28916726/the-nqo1-bioactivatable-drug-%C3%AE-lapachone-alters-the-redox-state-of-nqo1-pancreatic-cancer-cells-causing-perturbation-in-central-carbon-metabolism
#1
Molly A Silvers, Stanislaw Deja, Naveen Singh, Robert A Egnatchik, Jessica Sudderth, Xiuquan Luo, Muhammad S Beg, Shawn C Burgess, Ralph J DeBerardinis, David A Boothman, Matthew E Merritt
Many cancer treatments, such as those for managing recalcitrant tumors like pancreatic ductal adenocarcinoma, cause off-target toxicities in normal, healthy tissue, highlighting the need for more tumor-selective chemotherapies. β-Lapachone is bioactivated by NAD(P)H:quinone oxidoreductase 1 (NQO1). This enzyme exhibits elevated expression in most solid cancers and therefore is a potential cancer-specific target. β-Lapachone's therapeutic efficacy partially stems from the drug's induction of a futile NQO1-mediated redox cycle that causes high levels of superoxide, then peroxide formation, which damages DNA and causes hyperactivation of poly (ADP-ribose) polymerase (PARP), resulting in extensive NAD+/ATP depletion...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28833669/a-tumor-specific-cascade-amplification-drug-release-nanoparticle-for-overcoming-multidrug-resistance-in-cancers
#2
Mingzhou Ye, Yuxin Han, Jianbin Tang, Ying Piao, Xiangrui Liu, Zhuxian Zhou, Jianqing Gao, Jianghong Rao, Youqing Shen
A cascade amplification release nanoparticle (CARN) is constructed by the coencapsulation of β-lapachone and a reactive-oxygen-species (ROS)-responsive doxorubicin (DOX) prodrug, BDOX, in polymeric nanoparticles. Releasing β-lapachone first from the CARNs selectively increases the ROS level in cancer cells via NAD(P)H:quinone oxidoreductase-1 (NQO1) catalysis, which induces the cascade amplification release of DOX and overcomes multidrug resistance (MDR) in cancer cells, producing a remarkably improved therapeutic efficacy against MDR tumors with minimal side effects...
August 21, 2017: Advanced Materials
https://www.readbyqxmd.com/read/28829143/intermolecular-interactions-between-coencapsulated-drugs-inhibit-drug-crystallization-and-enhance-colloidal-stability-of-polymeric-micelles
#3
Ling Zhang, Hanzi Sun, Zhen Chen, Zhengsheng Liu, Niu Huang, Feng Qian
Novel "pairs" of drugs possessing pharmacological synergies could be encapsulated into polymeric micelles and exert superb therapeutic effects in vivo upon intravenous administration, with the prerequisite that the micelles remain stable. NADP(H) quinone oxidoreductase 1 (NQO1) inhibitors, such as β-lapachone (LPC) and tanshinone IIA (THA), are structurally and pharmacologically similar molecules that are poorly water-soluble, crystallize extremely fast, and demonstrate synergistic anticancer effect when used together with paclitaxel (PTX)...
September 1, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28762750/genome-scale-modeling-of-nadph-driven-%C3%AE-lapachone-sensitization-in-head-and-neck-squamous-cell-carcinoma
#4
Joshua E Lewis, Francesco Costantini, Jade Mims, Xiaofei Chen, Cristina M Furdui, David A Boothman, Melissa L Kemp
AIMS: The purpose of this study was to investigate differential NADPH production between radiation-sensitive and -resistant head and neck squamous cell carcinoma (HNSCC) cell lines and whether these differences are predictive of sensitivity to the chemotherapeutic β-lapachone. RESULTS: We have developed a novel human genome-scale metabolic modeling platform that combines transcriptomic, kinetic, thermodynamic, and metabolite concentration data. Upon incorporation of this information into cell line-specific models, we observed that the radiation-resistant HNSCC model redistributed flux through several major NADPH-producing reactions...
September 14, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28592850/nad-augmentation-ameliorates-acute-pancreatitis-through-regulation-of-inflammasome-signalling
#5
AiHua Shen, Hyung-Jin Kim, Gi-Su Oh, Su-Bin Lee, Seung Hoon Lee, Arpana Pandit, Dipendra Khadka, Seong-Kyu Choe, Sung Chul Kwak, Sei-Hoon Yang, Eun-Young Cho, Hyun-Seok Kim, Hail Kim, Raekil Park, Tae Hwan Kwak, Hong-Seob So
Acute pancreatitis (AP) is a complicated disease without specific drug therapy. The cofactor nicotinamide adenine dinucleotide (NAD(+)) is an important regulator of cellular metabolism and homeostasis. However, it remains unclear whether modulation of NAD(+) levels has an impact on caerulein-induced AP. Therefore, in this study, we investigated the effect of increased cellular NAD(+) levels on caerulein-induced AP. We demonstrated for the first time that the activities and expression of SIRT1 were suppressed by reduction of intracellular NAD(+) levels and the p53-microRNA-34a pathway in caerulein-induced AP...
June 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28580145/lysosome-oriented-dual-stage-ph-responsive-polymeric-micelles-for-%C3%AE-lapachone-delivery
#6
Yinjian Zhou, Ying Dong, Gang Huang, Yiguang Wang, Xiaonan Huang, Fayun Zhang, David A Boothman, Jinming Gao, Wei Liang
β-Lapachone (β-lap), a novel anticancer agent, is bioactivated by NADP(H):quinone oxidoreductase 1 (NQO1), an enzyme over-expressed in numerous tumors, including lung, pancreas, breast, and prostate cancers. Fast renal clearance and methemaglobinemia / hemolytic side-effects from the clinical formulation (β-lap-hydroxyl propyl-β-cyclodextrin complex) hindered its clinical translation. Here, we investigated a dual model pH responsive polymers for β-lap delivery. Three pH-sensitive linkages, including acylhydrazone, ketal and imine bonds for β-lap prodrug syntheses result in an aryl imine linkage the most optimal linkage...
December 14, 2016: Journal of Materials Chemistry. B, Materials for Biology and Medicine
https://www.readbyqxmd.com/read/28578385/%C3%AE-lapachone-suppresses-tumour-progression-by-inhibiting-epithelial-to-mesenchymal-transition-in-nqo1-positive-breast-cancers
#7
Yang Yang, Xianchun Zhou, Ming Xu, Junjie Piao, Yuan Zhang, Zhenhua Lin, Liyan Chen
NQO1 is a FAD-binding protein that can form homodimers and reduce quinones to hydroquinones, and a growing body of evidence currently suggests that NQO1 is dramatically elevated in solid cancers. Here, we demonstrated that NQO1 was elevated in breast cancer and that its expression level was positively correlated with invasion and reduced disease free survival (DFS) and overall survival (OS) rates. Next, we found that β-lapachone exerted significant anti-proliferation and anti-metastasis effects in breast cancer cell lines due to its effects on NQO1 expression...
June 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28346693/using-a-novel-nqo1-bioactivatable-drug-beta-lapachone-arq761-to-enhance-chemotherapeutic-effects-by-metabolic-modulation-in-pancreatic-cancer
#8
Muhammad Shaalan Beg, Xiumei Huang, Molly A Silvers, David E Gerber, Joyce Bolluyt, Venetia Sarode, Farjana Fattah, Ralph J Deberardinis, Matthew E Merritt, Xian-Jin Xie, Richard Leff, Daniel Laheru, David A Boothman
Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor versus associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H2 O2 ) levels; normal tissues are spared by low NQO1 and high catalase expression...
July 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28214631/discovery-of-quinone-directed-antitumor-agents-selectively-bioactivated-by-nqo1-over-cpr-with-improved-safety-profile
#9
Jinlei Bian, Xiang Li, Nan Wang, Xingsen Wu, Qidong You, Xiaojin Zhang
In this work, we mainly focused on discovering compounds with good selectivity for NQO1 over CPR. The NQO1-mediated two-electron reduction of compounds would kill cancer cells selectively, while CPR-mediated one-electron reduction would induce potential hepatotoxicity. Several novel quinone-directed antitumor agents were discovered as specific NQO1 substrates through structure-activity relationship studies. Among them, compound 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione (12b) emerged as the most specific substrate of the two-electron oxidoreductase NQO1 and could hardly be reduced by CPR...
March 31, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27986568/distinct-responses-of-compartmentalized-glutathione-redox-potentials-to-pharmacologic-quinones-targeting-nqo1
#10
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...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27960087/leveraging-an-nqo1-bioactivatable-drug-for-tumor-selective-use-of-poly-adp-ribose-polymerase-inhibitors
#11
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/27913299/the-inhibitory-effect-of-beta-lapachone-on-rankl-induced-osteoclastogenesis
#12
Dong Ryun Gu, Joon No Lee, Gi-Su Oh, Hyung Jin Kim, Min Seuk Kim, Seoung Hoon Lee
β-lapachone (β-L) is a substrate of reduced nicotinamide adenine dinucleotide (NADH): quinone oxidoreductase 1 (NQO1). NQO1 reduces quinones to hydroquinones using NADH as an electron donor and consequently increases the intracellular NAD+/NADH ratio. The activation of NQO1 by β-L has beneficial effects on several metabolic syndromes, such as obesity, hypertension, and renal injury. However, the effect of β-L on bone metabolism remains unclear. Here, we show that β-L might be a potent inhibitor of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27790277/increased-cellular-nad-level-through-nqo1-enzymatic-action-has-protective-effects-on-bleomycin-induced-lung-fibrosis-in-mice
#13
Gi-Su Oh, Su-Bin Lee, Anjani Karna, Hyung-Jin Kim, AiHua Shen, Arpana Pandit, SeungHoon Lee, Sei-Hoon Yang, Hong-Seob So
BACKGROUND: Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet...
October 2016: Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/27608947/nampt-inhibition-synergizes-with-nqo1-targeting-agents-in-inducing-apoptotic-cell-death-in-non-small-cell-lung-cancer-cells
#14
Hui-Ying Liu, Qing-Ran Li, Xue-Fang Cheng, Guang-Ji Wang, Hai-Ping Hao
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA (TSA) and β-lapachone (β-lap) induced a rapid depletion of NAD(+) pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death...
August 2016: Chinese Journal of Natural Medicines
https://www.readbyqxmd.com/read/27341379/synthesis-and-antitumor-activity-of-selenium-containing-quinone-based-triazoles-possessing-two-redox-centres-and-their%C3%A2-mechanistic-insights
#15
Eduardo H G da Cruz, Molly A Silvers, Guilherme A M Jardim, Jarbas M Resende, Bruno C Cavalcanti, Igor S Bomfim, Claudia Pessoa, Carlos A de Simone, Giancarlo V Botteselle, Antonio L Braga, Divya K Nair, Irishi N N Namboothiri, David A Boothman, Eufrânio N da Silva Júnior
UNLABELLED: Selenium-containing quinone-based 1,2,3-triazoles were synthesized using click chemistry, the copper catalyzed azide-alkyne 1,3-dipolar cycloaddition, and evaluated against six types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), PC3 (human prostate cells), SF295 (human glioblastoma cells), MDA-MB-435 (melanoma cells) and OVCAR-8 (human ovarian carcinoma cells). Some compounds showed IC50 values < 0.3 μM. The cytotoxic potential of the quinones evaluated was also assayed using non-tumor cells, exemplified by peripheral blood mononuclear (PBMC), V79 and L929 cells...
October 21, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27242267/%C3%AE-lapachone-increases-phase-ii-antioxidant-enzyme-expression-via-nqo1-ampk-pi3k-nrf2-are-signaling-in-rat-primary-astrocytes
#16
Jin-Sun Park, Yu-Young Lee, Jisun Kim, Hyemyung Seo, Hee-Sun Kim
β-Lapachone (β-LAP) is a naturally occurring quinine that exerts a number of pharmacological actions including antibacterial, antifungal, antimalarial, and antitumor activities. In the present study, we investigated whether β-LAP has an antioxidant effect in rat primary astrocytes. β-LAP suppressed intracellular reactive oxygen species (ROS) production induced by hydrogen peroxide and inhibited astroglial cell death. It also increased astrocytic expression of phase II antioxidant enzymes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), manganese superoxide dismutase (MnSOD), and catalase...
August 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27196777/nqo1-mediated-tumor-selective-lethality-and-radiosensitization-for-head-and-neck-cancer
#17
Long-Shan Li, Srilakshmi Reddy, Zhen-Hua Lin, Shuangping Liu, Hyunsil Park, Stephen G Chun, William G Bornmann, Joel Thibodeaux, Jingsheng Yan, Gaurab Chakrabarti, Xian-Jin Xie, Baran D Sumer, David A Boothman, John S Yordy
UNLABELLED: Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNC). However, the 5-year overall survival rate for locally advanced HNCs is approximately 50% and better therapeutic efficacy is needed. NAD(P)H: quinone oxidoreductase 1 (NQO1) is overexpressed in many cancers, and β-lapachone (β-lap), a unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) that synergize with IR to kill by programmed necrosis...
July 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27048660/%C3%AE-lapachone-induces-nad-p-h-quinone-oxidoreductase-1-and-oxidative-stress-dependent-heat-shock-protein-90-cleavage-and-inhibits-tumor-growth-and-angiogenesis
#18
Yougen Wu, Xue Wang, Siyu Chang, Weiqiang Lu, Mingyao Liu, Xiufeng Pang
UNLABELLED: β-Lapachone [β-lap; 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione] is a novel anticancer drug currently under investigation in phase I/II clinical trials. However, the mechanism underlying its clinical efficacy remains unclear. In this study, we found that β-lap provoked the cleavage of heat shock protein 90 (Hsp90) in NAD(P)H: quinone oxidoreductase-1 (NQO1)-expressing lung and prostate cancer cells as well as in primary human umbilical vein endothelial cells (HUVECs)...
June 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/26901461/using-dna-devices-to-track-anticancer-drug-activity
#19
Dimithree Kahanda, Gaurab Chakrabarti, Marc A Mcwilliams, David A Boothman, Jason D Slinker
It is beneficial to develop systems that reproduce complex reactions of biological systems while maintaining control over specific factors involved in such processes. We demonstrated a DNA device for following the repair of DNA damage produced by a redox-cycling anticancer drug, beta-lapachone (β-lap). These chips supported ß-lap-induced biological redox cycle and tracked subsequent DNA damage repair activity with redox-modified DNA monolayers on gold. We observed drug-specific changes in square wave voltammetry from these chips at therapeutic ß-lap concentrations of high statistical significance over drug-free control...
June 15, 2016: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/26803578/novel-naphtho-2-1-d-oxazole-4-5-diones-as-nqo1-substrates-with-improved-aqueous-solubility-design-synthesis-and-in-vivo-antitumor-evaluation
#20
Xiang Li, Jinlei Bian, Nan Wang, Xue Qian, Jing Gu, Tong Mu, Jun Fan, Xiuwen Yang, Shangzhen Li, Tingting Yang, Haopeng Sun, Qidong You, Xiaojin Zhang
A new series of ortho-naphthoquinone analogs of β-lapachone were designed, synthesized and evaluated. The biological results indicated that most of our compounds were efficient substrates for NQO1. The new scaffold with water-soluble side chain resulted in greater solubility under acidic condition compared to β-lapachone. Thus avoiding the use of hydroxylpropyl β-cyclodextrin which would finally cause the rapid drug clearance from the blood and dose-limiting toxicity in the form of hemolytic anemia. The most soluble and promising compound in this series was 2-((4-benzylpiperazin-1-yl)methyl)naphtho[2,1-d]oxazole-4,5-dione (3k), which inhibited cancer cell (NQO1-rich A549 cell line) growth at IC50 values of 4...
March 1, 2016: Bioorganic & Medicinal Chemistry
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