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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
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
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
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
A Young Kim, Kyeong-Hoon Jeong, Jae Ho Lee, Yup Kang, Soo Hwan Lee, Eun Joo Baik
Deregulation of glutamate homeostasis is associated with degenerative neurological disorders. Glutamate dehydrogenase (GDH) is important for glutamate metabolism and plays a central role in expanding the pool of tricarboxylic acid (TCA) cycle intermediate alpha-ketoglutarate (α-KG), which improves overall bioenergetics. Under high energy demand, maintenance of ATP production results in functionally active mitochondria. Here, we tested whether the modulation of GDH activity can rescue ischemia/reperfusion-induced neuronal death in an in vivo mouse model of middle artery occlusion and an in vitro oxygen/glucose depletion model...
January 6, 2017: Neuroscience
Won Hee Choi, Jiyun Ahn, Chang Hwa Jung, Young Jin Jang, Tae Youl Ha
There has been great interest in the browning of fat for the treatment of obesity. Although β-lapachone (BLC) has potential therapeutic effects on obesity, the fat-browning effect and thermogenic capacity of BLC on obesity have never been demonstrated. Here, we showed that BLC stimulated the browning of white adipose tissue (WAT), increased the expression of brown adipocyte-specific genes (e.g., uncoupling protein 1 [UCP1]), decreased body weight gain, and ameliorated metabolic parameters in mice fed a high-fat diet...
September 2016: Diabetes
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
Young-Joo Jeon, Woong Bang, Yung Hyun Choi, Jung-Hyun Shim, Jung-Il Chae
Lung cancer is the leading cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) is the most common pathological type with a reported frequency of about 85% of all cases. Despite recent advances in therapeutic agents and targeted therapies, the prognosis for NSCLC remains poor, and therefore it is important to identify the biological targets of this complex disease since a blockade of such targets would affect multiple downstream signaling cascades. β-Lapachone (β-Lap) is an antiproliferative agent that selectively induces apoptosis-related cell death in a variety of human cancer cells...
2015: Biological & Pharmaceutical Bulletin
Jason Z Li, Yuebin Ke, Hara P Misra, Michael A Trush, Y Robert Li, Hong Zhu, Zhenquan Jia
UNLABELLED: Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by NAD(P)H: quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16-F10 and hepatocellular carcinoma HepG2 cancer cells...
December 15, 2014: Toxicology and Applied Pharmacology
Shimrit Ohayon, Maya Refua, Adi Hendler, Amir Aharoni, Ashraf Brik
Deubiquitinases (DUBs) counteract ubiquitination by removing or trimming ubiquitin chains to alter the signal. Their diverse role in biological processes and involvement in diseases have recently attracted great interest with regard to their mechanism and inhibition. It has been shown that some DUBs are regulated by reactive oxygen species (ROS) in which the catalytic Cys residue undergoes reversible oxidation, hence modulating DUBs activity under oxidative stress. Reported herein for the first time, the observation that small molecules, which are capable of generating ROS efficiently, inhibit DUBs by selective and nonreversible oxidation of the catalytic Cys residue...
January 7, 2015: Angewandte Chemie
Sung Wook Park, Jin Hyoung Kim, Ko-Eun Kim, Moon Hee Jeong, Hyunsung Park, Bongju Park, Young-Ger Suh, Woo Jin Park, Jeong Hun Kim
Retinal neovascularization in retinopathy of prematurity (ROP) is the most common cause of blindness for children. Despite evidence that hypoxia inducible factor (HIF)-1α -VEGF axis is associated with the pathogenesis of ROP, the inhibitors of HIF-1α have not been established as a therapeutic target in the control of ROP pathophysiology. We investigated the hypothesis that degradation of HIF-1α as a master regulator of angiogenesis in hypoxic condition, using β-lapachone, would confer protection against hypoxia-induced retinopathy without affecting physiological vascular development in mice with oxygen-induced retinopathy (OIR), an animal model of ROP...
May 2014: Journal of Cellular and Molecular Medicine
Ki Jung Ahn, Hyung Sik Lee, Se Kyung Bai, Chang Won Song
Beta-lapachone (β-Lap; 3,4-dihydro-2, 2-dimethyl-2H-naphthol[1, 2-b]pyran-5,6-dione) is a novel anti-cancer drug under phase I/II clinical trials. β-Lap has been demonstrated to cause apoptotic and necrotic death in a variety of human cancer cells in vitro and in vivo. The mechanisms underlying the β-Lap toxicity against cancer cells has been controversial. The most recent view is that β-Lap, which is a quinone compound, undergoes two-electron reduction to hydroquinone form utilizing NAD(P)H or NADH as electron source...
June 2013: Radiation Oncology Journal
Soung Baek Jang, Dongju Kim, Seong Yeon Kim, Changhee Park, Ji Hoon Jeong, Hyo-Jeong Kuh, Jaehwi Lee
The aim of the present study was to examine the effect of micellar systems on the absorption of beta-lapachone (b-lap) through different intestinal segments using a single-pass rat intestinal perfusion technique. B-lap was solubilized in mixed micelles composed of phosphatidylcholine and sodium deoxycholate, and in sodium lauryl sulfate (SLS)-based conventional micelles. Both mixed micelles and SLS micelles improved the in situ permeability of b-lap in all intestinal segments tested although the mixed micellar formulation was more effective in increasing the intestinal absorption of b-lap...
February 2013: Korean Journal of Physiology & Pharmacology
Jeong-sook Lee, Ah Hyung Park, Sang-Hee Lee, Seoung-Hoon Lee, Jin-Hwan Kim, Suk-Jin Yang, Young Il Yeom, Tae Hwan Kwak, Dongyeop Lee, Seung-Jae Lee, Chul-Ho Lee, Jin Man Kim, Daesoo Kim
NADH-quinone oxidoreductase 1 (NQO1) modulates cellular NAD(+)/NADH ratio which has been associated with the aging and anti-aging mechanisms of calorie restriction (CR). Here, we demonstrate that the facilitation of NQO1 activity by feeding β-lapachone (βL), an exogenous NQO1 co-substrate, prevented age-dependent decline of motor and cognitive function in aged mice. βL-fed mice did not alter their food-intake or locomotor activity but did increase their energy expenditure as measured by oxygen consumption and heat generation...
2012: PloS One
A J Araújo, A A de Souza, E N da Silva Júnior, J D B Marinho-Filho, M A B F de Moura, D D Rocha, M C Vasconcellos, C O Costa, C Pessoa, M O de Moraes, V F Ferreira, F C de Abreu, A V Pinto, R C Montenegro, L V Costa-Lotufo, M O F Goulart
In this study, the cytotoxicity, genotoxicity and early ROS generation of 2,2-dimethyl-(3H)-3-(N-3'-nitrophenylamino)naphtho[1,2-b]furan-4,5-dione (QPhNO(2)) were investigated and compared with those of its precursor, nor-beta-lapachone (nor-beta), with the main goal of proposing a mechanism of antitumor action. The results were correlated with those obtained from electrochemical experiments held in protic (acetate buffer pH 4.5) and aprotic (DMF/TBABF(4)) media in the presence and absence of oxygen and with those from dsDNA biosensors and ssDNA in solution, which provided evidence of a positive interaction with DNA in the case of QPhNO(2)...
June 2012: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Liang Shen
Beta-Lapachone is a natural product with multiple pharmacological activities and mechanistic studies indicated that reactive oxygen species (ROS) generated by beta-lapachone play significant roles in its pharmacological actions. As photosensitization is an important ROS-generating pathway, in the present work, the photosensitization mechanisms of beta-lapachone are explored on the basis of density functional theory estimated triplet excited state characters. Starting from triplet excited state beta-lapachone, the possible generating pathways of 1O2 and O2*- are elucidated and the solvent effects on the photosensitizing reactions are also discussed...
November 2011: Natural Product Communications
Patricia A Garavaglia, Joaquín J B Cannata, Andrés M Ruiz, Dante Maugeri, Rosario Duran, Mónica Galleano, Gabriela A García
Drugs currently used for treatment of Trypanosoma cruzi infection, the ethiological agent of Chagas' disease, have shown side effects and variable efficiency. With the aim to describe parasite enzymes involved in the mechanisms of action of trypanocidal drugs and since it has been reported that reductases are crucial in their metabolism, we attempted to identify novel NADPH-dependent oxido-reductases from T. cruzi. The percolation of a soluble fraction of epimastigote lysates through a Cibacron Blue-Sepharose column followed by elution by NADPH yielded a predominant protein with an apparent molecular weight of 32 kDa...
October 2010: Molecular and Biochemical Parasitology
Sven Claessens, Pascal Habonimana, Norbert De Kimpe
Optimized epoxidation conditions of mono- and dialkylated naphthoquinones are presented. Based on the epoxidation protocol making use of H(2)O(2)/Na(2)CO(3), naphthoquinone epoxides are obtained in high yields. The optimized epoxidation conditions are applied in a short and high yielding synthesis of the pharmaceutically important beta-lapachone.
August 21, 2010: Organic & Biomolecular Chemistry
Jae Hyun Bae, Jin Wook Kim, Gi Ryang Kweon, Myoung Gyu Park, Kyeong-Hoon Jeong, Je Jong Kim, Du Geon Moon
INTRODUCTION: Adenosine monophosphate-activated protein kinase (AMPK) activation is suggested to relax smooth muscle by endothelial nitric oxide synthase (eNOS) phosphorylation. AIM: To assess the mechanism and effect of a novel AMPK activator, beta-lapachone, upon cavernosal smooth muscle relaxation and the therapeutic potential for erectile dysfunction. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with beta-lapachone...
August 2011: Journal of Sexual Medicine
Elvin Blanco, Erik A Bey, Chalermchai Khemtong, Su-Geun Yang, Jagadeesh Setti-Guthi, Huabing Chen, Chase W Kessinger, Kevin A Carnevale, William G Bornmann, David A Boothman, Jinming Gao
Lung cancer is the leading cause of cancer-related deaths with current chemotherapies lacking adequate specificity and efficacy. Beta-lapachone (beta-lap) is a novel anticancer drug that is bioactivated by NAD(P)H:quinone oxidoreductase 1, an enzyme found specifically overexpressed in non-small cell lung cancer (NSCLC). Herein, we report a nanotherapeutic strategy that targets NSCLC tumors in two ways: (a) pharmacodynamically through the use of a bioactivatable agent, beta-lap, and (b) pharmacokinetically by using a biocompatible nanocarrier, polymeric micelles, to achieve drug stability, bioavailability, and targeted delivery...
May 15, 2010: Cancer Research
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