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Lapachone

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https://www.readbyqxmd.com/read/29305142/oral-bioavailability-enhancement-of-%C3%AE-lapachone-a-poorly-soluble-fast-crystallizer-by-cocrystal-amorphous-solid-dispersion-and-crystalline-solid-dispersion
#1
Chengyu Liu, Zhengsheng Liu, Yuejie Chen, Zhen Chen, Huijun Chen, Yipshu Pui Feng Qian
The aim of this paper was to compare the in vitro dissolution and in vivo bioavailability of three solubility enhancement technologies for β-lapachone (LPC), a poorly water soluble compound with extremely high crystallization propensity. LPC cocrystal was prepared by co-grinding LPC with resorcinol. LPC crystalline and amorphous solid dispersions (CSD and ASD) were obtained by spray drying with Poloxamer 188 and HPMC-AS, respectively. The cocrystal structure was solved by single crystal x-ray diffraction. All formulations were characterized by WAXRD, DSC, POM and SEM...
January 2, 2018: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/29298345/redox-modulation-of-nqo1
#2
David Siegel, Donna D Dehn, Samantha S Bokatzian, Kevin Quinn, Donald S Backos, Andrea Di Francesco, Michel Bernier, Nichole Reisdorph, Rafael de Cabo, David Ross
NQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates. In cells, NQO1 participates in a number of binding interactions with other proteins and mRNA and these interactions may be influenced by the concentrations of reduced pyridine nucleotides. NAD(P)H can protect NQO1 from proteolytic digestion suggesting that binding of reduced pyridine nucleotides results in a change in NQO1 structure. We have used purified NQO1 to demonstrate the addition of NAD(P)H induces a change in the structure of NQO1; this results in the loss of immunoreactivity to antibodies that bind to the C-terminal domain and to helix 7 of the catalytic core domain...
2018: PloS One
https://www.readbyqxmd.com/read/29206496/development-of-solid-dispersions-of-%C3%AE-lapachone-in-peg-and-pvp-by-solvent-evaporation-method
#3
K M Dos Santos, R M Barbosa, F G A Vargas, E P de Azevedo, A C S Lins, C A Câmara, C F S Aragão, T F Moura, F N Raffin
β-lapachone (βlap) has shown potential use in various medical applications. However, its poor solubility has limited its systemic administration and clinical applications. The aim of this work is to develop solid dispersions of βlap using poly (ethylene glycol) (PEG 6000) and polyvinylpyrrolidone (PVP K30) as hydrophilic polymers and evaluate the dissolution rate in aqueous medium. Solid dispersions were prepared by solvent evaporation method using different weight ratios of βlap and hydrophilic polymer (1:1, 1:2 and 1:3)...
December 5, 2017: Drug Development and Industrial Pharmacy
https://www.readbyqxmd.com/read/29175018/understanding-serine-proteases-implications-on-leishmania-spp-lifecycle
#4
REVIEW
Carlos Roberto Alves, Raquel Santos de Souza, Karen Dos Santos Charret, Luzia Monteiro de Castro Cortes, Matheus Pereira de Sá Silva, Laura Barral Veloso, Luiz Filipe Gonçalves Oliveira, Franklin Souza-Silva
Serine proteases have significant functions over a broad range of biological processes relevant to the Leishmania spp lifecycle. Data gathered here present an update on the Leishmania spp serine proteases and the status of these enzymes as part of the parasite degradome. The serine protease genes (n = 26 to 28) in Leishmania spp, which encode proteins with a wide range of molecular masses (35 kDa-115 kDa), are described along with their degrees of chromosomal and allelic synteny. Amid 17 putative Leishmania spp serine proteases, only ∼18% were experimentally demonstrated as signal peptidases that remove the signal peptide from secretory pre-proteins, maturases of other proteins and with metacaspase-like activity...
November 21, 2017: Experimental Parasitology
https://www.readbyqxmd.com/read/29158665/pharmacokinetics-and-tolerability-of-mb12066-a-beta-lapachone-derivative-targeting-nad-p-h-quinone-oxidoreductase-1-two-independent-double-blind-placebo-controlled-combined-single-and-multiple-ascending-dose-first-in-human-clinical-trials
#5
Seokuee Kim, SeungHwan Lee, Joo-Youn Cho, Seo Hyun Yoon, In-Jin Jang, Kyung-Sang Yu
MB12066 is a molecule derived from β-lapachone that shown effects on obesity in previous studies. The present studies were conducted to evaluate the tolerability and pharmacokinetics (PK) of MB12066 after the oral administration of single and multiple doses to healthy volunteers. The study comprised 2 independent, randomized, double-blind, placebo-controlled, combined single and multiple ascending dose first-in-human clinical trials to evaluate the safety, tolerability and PK of MB12066 in healthy Korean volunteers...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29066863/pharmacokinetic-and-safety-evaluation-of-mb12066-an-nqo1-substrate
#6
Hae Won Lee, Sook Jin Seong, Boram Ohk, Woo Youl Kang, Mi-Ri Gwon, Bo Kyung Kim, Hyun-Ju Kim, Young-Ran Yoon
OBJECTIVE: This study evaluated the pharmacokinetics (PKs) and safety of a newly developed β-lapachone (MB12066) tablet, a natural NAD(P)H:quinone oxidoreductase 1 (NQO1) substrate, in healthy male volunteers. METHODS: In a randomized, double-blind, multiple-dose, two-treatment study, 100 mg MB12066 or placebo was given twice daily for 8 days to groups of eight or three fasted healthy male subjects, respectively, followed by serial blood sampling. Plasma concentrations for β-lapachone were determined using liquid chromatography-tandem mass spectrometry...
2017: Drug Design, Development and Therapy
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
#7
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 and then peroxide formation, which damages DNA and causes hyperactivation of poly(ADP-ribose) polymerase, resulting in extensive NAD(+)/ATP depletion...
November 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28871151/time-resolved-pharmacological-studies-using-automated-on-line-monitoring-of-five-parallel-suspension-cultures
#8
Ala A Alhusban, Michael C Breadmore, Nuri Gueven, Rosanne M Guijt
Early stage pharmacological studies rely on in vitro methodologies for screening and testing compounds. Conventional assays based on endpoint measurements provide limited information because the lack in temporal resolution may not determine the pharmacological effect at its maximum. We developed an on-line, automated system for near real-time monitoring of extracellular content from five parallel suspension cultures, combining cell density measurements with a high-resolution separations every 12 minutes for 4 days...
September 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28833669/a-tumor-specific-cascade-amplification-drug-release-nanoparticle-for-overcoming-multidrug-resistance-in-cancers
#9
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
#10
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)...
October 2, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28818447/on-the-synthesis-of-quinone-based-bodipy-hybrids-new-insights-on-antitumor-activity-and-mechanism-of-action-in-cancer-cells
#11
Talita B Gontijo, Rossimiriam P de Freitas, Flavio S Emery, Leandro F Pedrosa, José B Vieira Neto, Bruno C Cavalcanti, Claudia Pessoa, Aaron King, Fabio de Moliner, Marc Vendrell, Eufrânio N da Silva Júnior
Fluorescent quinone-based BODIPY hybrids were synthesised and characterised by NMR analysis and mass spectrometry. We measured their cytotoxic activity against cancer and normal cell lines, performed mechanistic studies by lipid peroxidation and determination of reduced (GSH) and oxidized (GSSG) glutathione, and imaged their subcellular localisation by confocal microscopy. Cell imaging experiments indicated that nor-β-lapachone-based BODIPY derivatives might preferentially localise in the lysosomes of cancer cells...
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28805467/protective-microencapsulation-of-%C3%AE-lapachone-using-porous-glass-membrane-technique-based-on-experimental-optimisation
#12
Ki Hyun Kim, Tuan-Ho Le, Hee Kyung Oh, Bora Heo, Jeonghyun Moon, Sangmun Shin, Seong Hoon Jeong
Even though β-lapachone is a novel drug with pharmacological activity, it has limitations including instability under light conditions. The main purpose of the study was to enhance the stability of β-lapachone using the microencapsulation method. The Shirasu porous glass membrane was used to achieve uniform-sized microcapsules. The prepared microcapsules were evaluated to investigate how process parameters affect the encapsulation efficiency, photostability and particle size distribution. The experimental design was conducted to obtain optimal formulations...
August 28, 2017: Journal of Microencapsulation
https://www.readbyqxmd.com/read/28798938/evidence-for-tissue-toxicity-in-balb-c-exposed-to-a-long-term-treatment-with-oxiranes-compared-to-meglumine-antimoniate
#13
Luiz Filipe Gonçalves Oliveira, Franklin Souza-Silva, Léa Cysne-Finkelstein, Kíssila Rabelo, Juliana Fernandes Amorim, Adriana de Souza Azevedo, Saulo Cabral Bourguignon, Vitor Francisco Ferreira, Marciano Viana Paes, Carlos Roberto Alves
Leishmaniasis remains a serious public health problem in developing countries without effective control, whether by vaccination or chemotherapy. Part of the failure of leishmaniasis control is due to the lack of new less toxic and more effective drugs able to eliminate both the lesions and the parasite. Oxiranes derived from naphthoquinones now being assayed are promising drugs for the treatment of this group of diseases. The predicted pharmacokinetic properties and toxicological profiles of epoxy-α-lapachone and epoxymethoxy-lawsone have now been compared to those of meglumine antimoniate, and histological changes induced by these drugs in noninfected BALB/c mice tissues are described...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28762750/genome-scale-modeling-of-nadph-driven-%C3%AE-lapachone-sensitization-in-head-and-neck-squamous-cell-carcinoma
#14
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/28700690/inactivation-of-human-dgat2-by-oxidative-stress-on-cysteine-residues
#15
Sunhee Jung, Miri Choi, Kwangman Choi, Eun Bin Kwon, Mingu Kang, Dong-Eun Kim, Hyejeong Jeong, Janghwan Kim, Jong Heon Kim, Mun Ock Kim, Sang-Bae Han, Sungchan Cho
Diacylglycerol acyltransferases (DGATs) have a crucial role in the biosynthesis of triacylglycerol (TG), the major storage form of metabolic energy in eukaryotic organisms. Even though DGAT2, one of two distinct DGATs, has a vital role in TG biosynthesis, little is known about the regulation of DGAT2 activity. In this study, we examined the role of cysteine and its oxidation in the enzymatic activity of human DGAT2 in vitro. Human DGAT2 activity was considerably inhibited not only by thiol-modifying reagents (NEM and IA) but also by ROS-related chemicals (H2O2 and β-lapachone), while human DGAT1 and GPAT1 were little affected...
2017: PloS One
https://www.readbyqxmd.com/read/28675505/supramolecular-interactions-between-%C3%AE-lapachone-with-cyclodextrins-studied-using-isothermal-titration-calorimetry-and-molecular-modeling
#16
Francisco H Xavier-Junior, Marcelo M Rabello, Marcelo Z Hernandes, Marília E S Dias, Otoni H M S Andrada, Beatriz P Bezerra, Alejandro P Ayala, Nereide S Santos-Magalhães
Supramolecular interactions between β-lapachone (β-lap) and cyclodextrins (CDs) were investigated by isothermal titration calorimetry. The most favorable host: guest interaction was characterized using X-ray powder diffraction (XRD), differential scanning calorimetry and thermogravimetry (DSC/TG), spectroscopy (FT-IR), spectroscopy (2D ROESY) nuclear magnetic resonance (NMR), and molecular modeling. Phase solubility diagrams showed β-, HP-β-, SBE-β-, γ-, and HP-γ-CDs at 1.5% (w/w) allowed an increase in apparent solubility of β-lap with enhancement factors of 12...
July 4, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28592850/nad-augmentation-ameliorates-acute-pancreatitis-through-regulation-of-inflammasome-signalling
#17
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/28586252/lapachol-and-lapachone-analogs-a-journey-of-two-decades-of-patent-research-1997-2016
#18
REVIEW
Hidayat Hussain, Ivan R Green
Lapachol (1), β-lapachone (2) and α-lapachone (3) are three well-studied natural products isolated from Tabebuia impetiginosa having most interesting chemodiversity and demonstrating diverse biological effects. Areas covered: The current review summarizes the recent and past discovery of chemotherapeutic agents based on the compounds 1-3. This review presents an overview of patents filed over the past two decades (1997 to 2016) mostly relating to the anticancer effects of these lapachol and lapachone analogues...
October 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28580145/lysosome-oriented-dual-stage-ph-responsive-polymeric-micelles-for-%C3%AE-lapachone-delivery
#19
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
#20
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
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