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Dong Wook Kim, Je-Yoel Cho
Cancer stem cells (CSCs) exhibit self-renewal activity and give rise to other cell types in tumors. Due to the infinite proliferative potential of CSCs, drugs targeting these cells are necessary to completely inhibit cancer development. The β-lapachone (bL) compound is widely used to treat cancer development; however, its effect on cancer stem cells remain elusive. Thus, we investigated the effect of bL on mammosphere formation using breast-cancer stem-cell (BCSC) marker-positive cells, MDA-MB-231. MDA-MB-231 cells, which are negative for reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H):quinone oxidoreductase (NQO1) expression, were constructed to stably express NQO1 (NQO1 stable cells)...
November 30, 2018: International Journal of Molecular Sciences
Ana Cristina S Bombaça, Paula G Viana, Augusto C C Santos, Thaissa L Silva, Aline Beatriz M Rodrigues, Ana Carolina R Guimarães, Marilia O F Goulart, Eufrânio N da Silva Júnior, Rubem F S Menna-Barreto
Chagas disease is caused by the hemoflagellate protozoa Trypanosoma cruzi and is one of the most important neglected tropical diseases, especially in Latin American countries, where there is an association between low-income populations and mortality. The nitroderivatives used in current chemotherapy are far from ideal and present severe limitations, justifying the continuous search for alternative drugs. Since the1990s, our group has been investigating the trypanocidal activity of natural naphthoquinones and their derivatives, and three naphthoimidazoles (N1, N2 and N3) derived from β-lapachone were found to be most effective in vitro...
November 14, 2018: Free Radical Biology & Medicine
María Julia Lamberti, Ana Belén Morales Vasconsuelo, Marianela Chiaramello, Vitor Francisco Ferreira, Milena Macedo Oliveira, Sabrina Baptista Ferreira, Viviana Alicia Rivarola, Natalia Belén Rumie Vittar
The elevated expression of NQO1 in many human solid tumors along with its ability to activate quinone-based anticancer agents makes it an excellent target for enzyme-directed drug development. NQO1 plays an important role in melanogenesis and given its correlation with a poor patient outcome we propose this enzyme as an intriguing target for molecular-based therapeutic regimen against melanoma. Unfortunately, the natural product β-Lapachone (β-Lap), whose antitumor activity is based on NQO1, reported dose-limiting toxicity which hampered its pre-clinical and clinical use...
December 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
David E Gerber, M Shaalan Beg, Farjana Fattah, Arthur E Frankel, Oluwatomilade Fatunde, Yull Arriaga, Jonathan E Dowell, Ajit Bisen, Richard D Leff, Claudia C Meek, William C Putnam, Raja Reddy Kallem, Indhumathy Subramaniyan, Ying Dong, Joyce Bolluyt, Venetia Sarode, Xin Luo, Yang Xie, Brian Schwartz, David A Boothman
BACKGROUND: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a β-lapachone (β-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death. METHODS: We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression...
October 2018: British Journal of Cancer
Tiago Rodrigues, Markus Werner, Jakob Roth, Eduardo H G da Cruz, Marta C Marques, Padma Akkapeddi, Susana A Lobo, Andreas Koeberle, Francisco Corzana, Eufrânio N da Silva Júnior, Oliver Werz, Gonçalo J L Bernardes
Using machine learning, targets were identified for β-lapachone. Resorting to biochemical assays, β-lapachone was validated as a potent, ligand efficient, allosteric and reversible modulator of 5-lipoxygenase (5-LO). Moreover, we provide a rationale for 5-LO modulation and show that inhibition of 5-LO is relevant for the anticancer activity of β-lapachone. This work demonstrates the power of machine intelligence to deconvolute complex phenotypes, as an alternative and/or complement to chemoproteomics and as a viable general approach for systems pharmacology studies...
September 14, 2018: Chemical Science
Marcília P Costa, Anderson C S Feitosa, Fátima C E Oliveira, Bruno C Cavalcanti, Gleiston G Dias, Ewerton W S Caetano, Francisco A M Sales, Valder N Freire, Stefano Di Fiore, Rainer Fischer, Luiz O Ladeira, Eufrânio N da Silva Júnior, Claudia Pessoa
In this work, we characterize nor-β-lapachone-loaded (NβL-loaded) microcapsules prepared using an emulsification/solvent extraction technique. Features such as surface morphology, particle size distribution, zeta potential, optical absorption, Raman and Fourier transform infrared spectra, thermal analysis data, drug encapsulation efficiency, drug release kinetics and in vitro cytotoxicity were studied. Spherical microcapsules with a size of 1.03 ± 0.46 μm were produced with an encapsulation efficiency of approximately 19%...
October 1, 2017: MedChemComm
Dimithree Kahanda, Naveen Singh, David A Boothman, Jason D Slinker
There is a great need to track the selectivity of anticancer drug activity and to understand the mechanisms of associated biological activity. Here we focus our studies on the specific NQO1 bioactivatable drug, ß-lapachone, which is in several Phase I clinical trials to treat human non-small cell lung, pancreatic and breast cancers. Multi-electrode chips with electrochemically-active DNA monolayers are used to track anticancer drug activity in cellular lysates and correlate cell death activity with DNA damage...
November 15, 2018: Biosensors & Bioelectronics
Charlotte M S Detremmerie, Susan W S Leung, Paul M Vanhoutte
Earlier studies on isolated arteries demonstrated that the para-quinone thymoquinone, like acute hypoxia, induces augmentation of contractions, depending on biased activity of soluble guanylyl cyclase (sGC), generating inosine-3',5'-cyclic monophosphate (cyclic IMP) rather than guanosine-3',5'-cyclic monophosphate (cyclic GMP). NAD(P)H:quinone oxidoreductase 1 (NQO-1), the enzyme responsible for biotransformation of quinones into hydroquinones, was examined for its involvement in these endothelium-dependent augmentations, establishing a link between the metabolism of quinones by NQO-1 and biased sGC activity...
November 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
Xin Li, Xiaoqian Jia, Hu Niu
Background: Multidrug resistance is responsible for the poor outcome in breast cancer therapy. Lapa is a novel therapeutic agent that generates ROS through the catalysis of the NAD(P) H:quinone oxidoreductase-1 (NQO1) enzyme which significantly facilitate the intracellular accumulation of the co-delivered DOX to overcome MDR in cancer cells. Purpose: Herein, in our study, nanostructured lipid carrier (NLC) co-delivering β-lapachone (Lapa) and doxorubicin (DOX) was developed (LDNLC) with the aim to overcome the multidrug resistance (MDR) in breast cancer therapy...
2018: International Journal of Nanomedicine
Hauke Löcken, Cinzia Clamor, Klaus Müller
Napabucasin (6) and its angularly anellated isomer (7), for which the synthesis is described, together with related plant-derived naphthoquinones, were evaluated in vitro against human breast cancer (MDA-MB-231) and chronic myelogenous leukemia (K562) cells. As observed for β-lapachone (3), the active naphthoquinones all induced apoptosis in a cell-cycle-independent fashion. In contrast to the pyran-fused β-lapachone (3), however, the most potent furan-fused naphthoquinones were able to redox cycle and generate superoxide in cell-based assays, which was independent of NAD(P)H:quinone oxido-reductase 1...
July 27, 2018: Journal of Natural Products
Silvia Helena Cardoso, Cleidijane Rodrigues de Oliveira, Ari Souza Guimarães, Jadiely Nascimento, Julianderson de Oliveira Dos Santos Carmo, Jamylle Nunes de Souza Ferro, Ana Carolina de Carvalho Correia, Emiliano Barreto
Naphthoquinone derivatives have various pharmacological properties. Here, we describe the synthesis of new 1,4-naphthoquinone derivatives inspired by lawsone and β-lapachone and their effects on both migration of fibroblasts in vitro and dermal wound healing in diabetic mice. NMR and FTIR spectroscopy aided characterization of chemical composition and demonstrated the molecular variations after the synthesis of four different derivatives, namely 2-bromo-1,4-naphthoquinone (termed derivative S3), 2-N-phenylamino-1,4-naphthoquinone (derivative S5), 2-N-isonicotinoyl-hydrazide-1,4-naphthoquinone (derivative S6), and 1-N-isonicotinoyl-hydrazone-[2-hydroxy-3-(3-methyl-2-butenyl)]-1,4-naphthoquinone (derivative S7)...
August 1, 2018: Chemico-biological Interactions
Laura Anaissi-Afonso, Sandra Oramas-Royo, Jessel Ayra-Plasencia, Patricia Martín-Rodríguez, Jonay García-Luis, Isabel Lorenzo-Castrillejo, Leandro Fernández-Pérez, Ana Estévez-Braun, Félix Machín
Naphthoquinones are among the most active natural products obtained from plants and microorganisms. Naphthoquinones exert their biological activities through pleiotropic mechanisms that include reactivity against cell nucleophiles, generation of reactive oxygen species (ROS), and inhibition of proteins. Here, we report a mechanistic antiproliferative study performed in the yeast Saccharomyces cerevisiae for several derivatives of three important natural naphthoquinones: lawsone, juglone, and β-lapachone. We have found that (i) the free hydroxyl group of lawsone and juglone modulates toxicity; (ii) lawsone and juglone derivatives differ in their mechanisms of action, with ROS generation being more important for the former; and (iii) a subset of derivatives possess the capability to disrupt mitochondrial function, with β-lapachones being the most potent compounds in this respect...
August 17, 2018: ACS Chemical Biology
Mijung Lee, Jae-Jun Ban, Jin-Young Chung, Wooseok Im, Manho Kim
Huntington's disease (HD) is one of the most devastating genetic neurodegenerative disorders with no effective medical therapy. β-Lapachone (βL) is a natural compound obtained from the bark of the Lapacho tree and has been reported to have beneficial effects on various diseases. Sirt1 is a deacetylase of the sirtuin family and deacetylates proteins including the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) which is associated with mitochondrial respiration and biogenesis...
2018: PloS One
Xuelian Cui, Liyan Chen, Jie Sun, Yixuan Wang, Zhenhua Lin
Objective To investigate the effect and molecular mechanism of β-lapachone combined with NVP-BEZ235 on the proliferation and migration of BGC-823 human gastric cancer cells. Methods BGC-823 cells were randomly divided into four groups: control group, 1 μmol/L β-lapachone group, 50 nmol/L NVP-BEZ235 group and 1 μmol/L β-lapachone combined with 50 nmol/L NVP-BEZ235 group. The proliferation of cells was determined using the MTT assay and colony formation assay. The expression levels of proliferation-related proteins phosphorylated AKT (p-AKT), phosphorylated NF-κB (p-NF-κB), phosphorylated extracellular signal-regulated kinase (p-ERK) and cyclin D1 were detected by Western blotting...
February 2018: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
Hamideh Mahmoudinasab, Mostafa Saadat
β-Lapachone (β-Lap), morphine (Mor), and electromagnetic field (EMF) generate reactive oxygen species. The goal of the present study was to examine the effects of Mor and EMF, in combination with β-Lap on the cell growth inhibition and expression of several antioxidant genes. The 0.50 mT intensity of 50 Hz EMF and two exposure conditions ("15 min field-on/15 min field-off" and "30 min field-on continuously") on SH-SY5Y cells were used. The effects of Mor and EMF, in combination with β-Lap on cell growth inhibition and the expression levels of several antioxidant genes (NQO1, NQO2, SOD1, SOD2, CAT, GSTO1, GSTM2, GSTM3, GSTP1, MGST1, MGST3) in SH-SY5Y cells were measured...
June 2018: Molecular Biology Reports
D C Moraes, J A R Curvelo, C A Anjos, K C G Moura, M C F R Pinto, M B Portela, R M A Soares
BACKGROUND: Candida albicans is the most important fungal pathogen that causes infections in humans, and the search for new therapeutic strategies for its treatment is essential. OBJECTIVE: The aim of this study was to evaluate the activity of seven naphthoquinones (β-lapachone, β-nor-lapachone, bromide-β-lapachone, hydroxy-β-lapachone, α-lapachone, α-nor-lapachone and α-xyloidone) on the growth of a fluconazole-resistant C. albicans oral clinical isolate and the effects of these compounds on the viability of mammalian cells, on yeast's morphogenesis, biofilm formation and cell wall mannoproteins availability...
June 2018: Journal de Mycologie Médicale
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
Patricia Andrea Garavaglia, María Fernanda Rubio, Marc Laverrière, Laura Mónica Tasso, Laura Edith Fichera, Joaquín J B Cannata, Gabriela Andrea García
Several ortho-naphthoquinones (o-NQs) have trypanocidal activity against Trypanosoma cruzi, the aetiological agent of Chagas disease. Previously, we demonstrated that the aldo-keto reductase from this parasite (TcAKR) reduces o-NQs, such as β-lapachone (β-Lap) and 9,10-phenanthrenequinone (9,10-PQ), with concomitant reactive oxygen species (ROS) production. Recent characterization of TcAKR activity and expression in two T. cruzi strains, CL Brener and Nicaragua, showed that TcAKR expression is 2.2-fold higher in CL Brener than in Nicaragua...
August 2018: Parasitology
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...
March 2018: European Journal of Pharmaceutics and Biopharmaceutics
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
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