Evaluation of the in vitro activity and in vivo bioavailability of realgar nanoparticles prepared by cryo-grinding

Wu, Jinzhu; Ho, Paul C.

doi:10.1016/j.ejps.2006.05.002

Cited by 101 publications

(59 citation statements)

References 27 publications

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“…Basically, realgar is a mineral with very low solubility in water and therefore leakage of arsenic from remedy is the question of bioavailability. It was shown that from some remedies like An Gong Niu Huang Wan release less arsenic than realgar while others like Liu Shen Wan show enhanced leaching of the arsenic [6].In the present study we used realgar nanosuspension, which was prepared by milling in order to improve its solubility as reported previously our experiments and those of others [12,14]. Our NP realgar IC 50 data in melanoma cell lines are in line not only with recently published conclusion that nanosize scaled realgar particles have enhanced cytotoxicity [13], but also with observation that their IC 50 values are even lower than IC 50 values for ATO [11,14].…”

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confidence: 99%

“…Several physical, chemical or biological procedures are proposed to improve the solubility of realgar [9][10][11]. Among them, highenergy milling belongs to one of the most promising tools for improvement of realgar solubility due to the decreasing of particle diameter to the nanosize scale [12][13][14].Arsenic trioxide (ATO, As 2 O 3 ) appeared as a small reactive molecule with high affinity for sulfhydryl groups of biomolecules like glutathione and cysteinyl residues in proteins. There 701 REALGAR NANOPARTICLES is a wide spectrum of ATO effects, such as HIF-dependent stimulation of angiogenesis, the expression of BH3-only proteins, HSP90 or 14-3-3ζ-mediated induction of apoptosis, Syk kinase-related activation of neutrophil toxicity and many others [15][16][17][18].…”

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confidence: 99%

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Realgar (As4S4) nanoparticles and arsenic trioxide (As2O3) induced autophagy and apoptosis in human melanoma cells in vitro

Pastorek¹,

Gronesova²,

Cholujová³

et al. 2014

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The aim of the present study was to compare the effect of realgar nanoparticles and arsenic trioxide (ATO) on viability, DNA damage, proliferation, autophagy and apoptosis in the human melanoma cell lines BOWES and A375. The application of various flow cytometric methods for measurements cell viability, DNA cell cycle, mitochondrial potential, lysosomal activity, and intracellular content of glutathione was used. In addition, quantitative PCR, western blotting and multiplex bead array analyses were applied for evaluation of redox stress, autophagic flux, and cell signaling alterations.The results showed that realgar treatment of studied cells caused modulation of cell proliferation, induced a block in G2/M phase of the cell cycle and altered phosphorylation of IκB, Akt, ERK1/2, p38, and JNK kinases, as well as decreased mitochondrial membrane potential. Additionally, it appeared that induction of cell death by both realgar and ATO was dose-dependent, when lower (0.3 µM) dosage increased lysosomal activity and induced autophagy and higher (1.25 µM) concentration resulted in the appearance of apoptosis, while pan-caspase inhibitor attenuated more efficiently realgar-than ATO-induced cell death. Furthermore, low concentrations of ATO and realgar nanoparticles increased the content of intracellular glutathione and elevated γ-H2AX expression confirmed DNA damage preferentially at higher concentrations of both drugs used. Further analysis revealed slight differences in time-dependent phosphorylation pattern due to both realgar and ATO treatments, while significant differences were noticed between cell lines.In conclusion, realgar nanoparticles and ATO treatment induced dose-dependent activation of autophagy and apoptosis in both melanoma cell lines, when autophagy flux was determined at lower drug concentrations and the switch to apoptosis occurred at higher concentrations of both arsenic forms.Key words : realgar, autophagy, cell cycle, DNA damage, Nrf2, chloroquine, glutathione Arsenic has been accepted to be a poison for years and it is generally considered as an extremely effective environmental co-carcinogen for some human malignancies, especially for skin and lung cancer [1]. The toxicity of arsenicals depends on their chemical states, exposure dose, the biological species, age and gender, as well as on individual susceptibilities, genetic and nutritional factors [2]. Largely, to living organisms methylated trivalent arsenicals are more toxic and pentavalent metabolites are less toxic than arsenite (iAs III ) [3,4]. In 2002, a pilot clinical study of pure realgar in treatment of patients with APL was conducted in China, and impressive responses were achieved and reported [5]. Realgar is a mineral composed mainly of tetra-arsenic tetra-sulfide (As 4 S 4 ), which is also called red arsenic due to its a deep red color (Xionghuang in Chinese). Low solubility of arsenic in realgar, using water as a solvent (0.4%), can be increased to approximately 1.5% by leaching in artificial body fluid [6]. Higher proportion of...

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Realgar (As4S4) nanoparticles and arsenic trioxide (As2O3) induced autophagy and apoptosis in human melanoma cells in vitro

Pastorek¹,

Gronesova²,

Cholujová³

et al. 2014

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“…NPs can be synthesised by a solution-liquid-solid method or a cryo-grinding method [8]. By means of these above-mentioned methods, the formation of nanorealgar always resulted in conventional colloids [9]. Due to the low stability of realgar NPs in aqueous solution, they tended to aggregate leading to broad distributions of particle size [10].…”

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confidence: 99%

Preparation, characterisation and antimicrobial activities of polymer/realgar nanocomposites

Cheng

Zhang

2013

Journal of Experimental Nanoscience

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Preparation and study of homogeneous nanoparticles (NPs) have been an important area of research in recent years. In this work, we describe a polymerprotected method for the preparation and formation of realgar nanocomposites with various average diameters. Two types of macromolecules were selected and their interactions with nanorealgar were studied by spectrometric methods. It is found that the starch has a significant effect on the formation and growth of homogeneous nanorealgar with an average diameter of 30 nm. In the case of using polyvinylpyrrolidone (PVP) as a protecting polymer, the realgar NP size is in the range of 20-80 nm, with an average value of 55 nm. The polymer-protected nanorealgar shows superior antimicrobial activity against Escherichia coli and Staphylococcus aureus, whereas the bulky realgar colloid formed in aqueous solution has much less antimicrobial activity. The antimicrobial activity followed the order As 4 S 4 -starch NPs 4 As 4 S 4 -PVP NPs 4 As 4 S 4 NPs, which suggests small realgar NPs are more favourable.

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“…The poor solubility of realgar limits its clinical applications (9) and presents a major challenge in cancer chemotherapy (10). The realgar nanoparticles (11)(12)(13) and realgar bioleaching solution (14) are more effective compared to crude realgar in antitumor studies, indicative of smaller sizes of realgar being preferable to achieve a more efficient bioavailability (9). Thus, realgar quantum dots (RQDs; 5.48±1.09 nm) were prepared in our previous study using a modified method (15).…”

Section: Introductionmentioning

confidence: 99%

Realgar quantum dots induce apoptosis and necrosis in HepG2 cells through endoplasmic reticulum stress

et al. 2015

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Abstract. Realgar (As 4 S 4 ) has been used in traditional Chinese medicines for treatment of malignancies. However, the poor water solubility of realgar limits its clinical application. To overcome this problem, realgar quantum dots (RQDs; 5.48±1.09 nm) were prepared by a photoluminescence method. The mean particle size was characterized by high-resolution transmission electron microscopy and scanning electron microscopy. Our recent studies revealed that the RQDs were effective against tumor growth in tumor-bearing mice without producing apparent toxicity. The present study investigated their anticancer effects and mechanisms in human hepatocellular carcinoma (HepG2) cells. The HepG2 cells and human normal liver (L02) cells were used to determine the cytotoxicity of RQDs. The portion of apoptotic and dead cells were measured by flow cytometry with Annexin V-fluorescein isothiocyanate/propidium iodide double staining. Apoptosis-related proteins and genes were examined by western blot analysis and reverse transcription-quantitative polymerase chain reaction, and the mitochondrial membrane potential was assayed by confocal microscope with JC-1 as a probe. RQDs exhibited cytotoxicity in a concentration-dependent manner and HepG2 cells were more sensitive compared with normal L02 cells. At 15 µg/ml, 20% of the cells were apoptotic, while 60% of the cells were necrotic at 30 µg/ml. The anti-apoptosis protein Bcl-2 was dose-dependently decreased, while pro-apoptotic protein Bax was increased. There was a loss of mitochondrial membrane potential and expression of the stress genes C/EBP-homologous protein 10 and glucose-regulated protein 78 was increased by RQDs. RQDs were effective in the inhibition of HepG2 cell proliferation and this effect was due to induction of apoptosis and necrosis through endoplasmic reticulum stress. IntroductionThe use of arsenic in China can be traced back thousands of years. Arsenic and arsenic salts, including orpiment, realgar and arsenolite, were fundamental ingredients in certain cancer treatments (1). The Fowler's solution (1% potassium arsenite) was used in the treatment of malignant diseases, such as leukemia and Hodgkin's disease, by numerous physicians in the 19-20th centuries (1). Arsenic trioxide (As 2 O 3 ) has emerged as the first-line therapy in the treatment of acute promyelocytic leukemia (APL); however, the toxicity hinders its clinical applications (2,3).Realgar contains >90% arsenic sulfide and is widely used externally and internally in a number of traditional medicine recipes in China (4). For example, realgar in combination with Indigo naturalis and Salvia miltiorrhiza is effective against APL (5), and targets RING-type E3 ligase c-CBL to induce degradation of BCR-Abl in chronic myelogenous leukemia (6). Realgar also enhances the antitumor effects of imatinib (7). Results from multicenter clinical trials using oral realgar formulations plus intravenous As 2 O 3 against hematological malignancy are promising (8).However, realgar is insoluble in water, resulting in poor ...

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Evaluation of the in vitro activity and in vivo bioavailability of realgar nanoparticles prepared by cryo-grinding

Cited by 101 publications

References 27 publications

Realgar (As4S4) nanoparticles and arsenic trioxide (As2O3) induced autophagy and apoptosis in human melanoma cells in vitro

Realgar (As4S4) nanoparticles and arsenic trioxide (As2O3) induced autophagy and apoptosis in human melanoma cells in vitro

Preparation, characterisation and antimicrobial activities of polymer/realgar nanocomposites

Realgar quantum dots induce apoptosis and necrosis in HepG2 cells through endoplasmic reticulum stress

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