scholarly journals Effect of structure in ionized albumin – based nanoparticle: Characterisation, Emodin interaction, and in vitro cytotoxicity

2019 ◽  
Author(s):  
Macarena Siri ◽  
Maria Julieta Fernandez Ruocco ◽  
Estefanía Achilli ◽  
Malvina Pizzuto ◽  
Juan F. Delgado ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Ex Vivo ◽  
Cancer Cell Lines ◽  
In Vitro Cytotoxicity ◽  
Haemolytic Activity ◽  
Hydrodynamic Diameter ◽  
Kinetic Properties ◽  
Experimental Conditions

AbstractA γ–irradiated bovine albumin serum based nanoparticle was characterised structurally, and functionally. The nanoparticle was characterised by A.F.M, D.L.S, zeta potential, T.E.M., gel-electrophoresis, spectroscopy (UV-Vis, Fluorescence, FT-IR, and CD). Its stability was studied under adverse experimental conditions: pH values, chaotropic agents, and ionic strength and stability studies against time were mainly carried out by fluorescence spectroscopy following the changes in the tryptophan environment in the nanoparticle. Its function was studied by the interaction of the NP with the hydrophobic drug Emodin was studied. The binding and kinetic properties of the obtained complex were tested by biophysical methods as well as its toxicity in tumour cells.According to its biophysics, the nanoparticle is a spherical nanosized vehicle with a hydrodynamic diameter of 70 nm. Data obtained describe the nanoparticle alone as nontoxic for cancer cell lines. When combined with Emodin, the bioconjugate proved to be more active on MCF-7 and PC-3 cancer cell lines than the nanoparticle alone. No haemolytic activity was found when tested against ex vivo red blood cells. The stability of the albumin nanoparticle is based on a competition between short-range attraction forces and long-range repulsion forces. The nanoparticle showed similar behaviour as albumin against pH while improving its stability in urea and tween 80. It was stable up to 15 days and presented no protein degradation in solutions up to 2 M salt concentration. Significantly, the albumin aggregate preserves the main activity-function of albumin and improved characteristics as an excellent carrier of molecules.Graphical Abstract

scholarly journals The Synthesis, Characterization, Cytotoxic Activity Assessment and Structure–Activity Relationship of 4-Aryl-6-(2,5-dichlorothiophen-3-yl)-2-methoxypyridine-3-carbonitriles

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4072
Author(s):  
Al-Refai ◽  
Ibrahim ◽  
Azmi ◽  
Osman ◽  
Bakar ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
In Vitro Cytotoxicity ◽  
Basic Medium ◽  
Condensation Process ◽  
Cytotoxicity Activities ◽  
Cytotoxicity Assessment ◽  
Relationship Of

A series of 2-methoxypyridine-3-carbonitrile (5a–i)-bearing aryl substituents were successfully synthesized in good yields by the condensation of chalcones (4a–i) with malononitrile in basic medium. The condensation process, in most cases, offers a route to a variety of methoxypyridine derivatives (6a–g) as side products in poor yields. All new compounds were fully characterized using different spectroscopic methods. Mass ESI-HMRS measurements were also performed. Furthermore, these compounds were screened for their in vitro cytotoxicity activities against three cancer cell lines; namely, those of the liver (line HepG2), prostate (line DU145) and breast (line MBA-MB-231). The cytotoxicity assessment revealed that compounds 5d, 5g, 5h and 5i exhibit promising antiproliferative effects (IC50 1–5 µM) against those three cancer cell lines.

scholarly journals In VitroGrowth Inhibitory Activities of Natural Products from Irciniid Sponges against Cancer Cells: A Comparative Study

2016 ◽  
Vol 2016 ◽  
pp. 1-6
Author(s):  
Yosr BenRedjem Romdhane ◽  
Monia Elbour ◽  
Marianna Carbone ◽  
Maria Letizia Ciavatta ◽  
Margherita Gavagnin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Antimicrobial Properties ◽  
Human Tumor ◽  
Cancer Cell Lines ◽  
Marine Sponges ◽  
Inhibitory Effects ◽  
Experimental Conditions ◽  
Growth Inhibitory

Marine sponges of the Irciniidae family contain both bioactive furanosesterterpene tetronic acids (FTAs) and prenylated hydroquinones (PHQs). Both classes of compounds are known for their anti-inflammatory, antioxidant, and antimicrobial properties and known to display growth inhibitory effects against various human tumor cell lines. However, the different experimental conditions of the reportedin vitrobioassays, carried out on different cancer cell lines within separate studies, prevent realistic actual discrimination between the two classes of compounds from being carried out in terms of growth inhibitory effects. In the present work, a chemical investigation of irciniid sponges from Tunisian coasts led to the purification of three known FTAs and three known PHQs. Thein vitrogrowth inhibitory properties of the six purified compounds have been evaluated in the same experiment in a panel of five human and one murine cancer cell lines displaying various levels of sensitivity to proapoptotic stimuli. Surprisingly, FTAs and PHQs elicited distinct profiles of growth inhibitory-responses, differing by one to two orders of magnitude in favor of the PHQs in all cell lines. The obtained comparative results are discussed in the light of a better selection of drug candidates from natural sources.

Further Preclinical Studies with APR-246, a Novel Anticancer Compound Currently in Clinical Trials for Hematological Malignancies and Prostate Cancer.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3773-3773
Author(s):  
Nina Mohell ◽  
Charlotta Liljebris ◽  
Jessica Alfredsson ◽  
Ylva Lindman ◽  
Maria Uustalu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ex Vivo ◽  
Cancer Cell Lines ◽  
Solid Cancer ◽  
Dependent Manner

Abstract Abstract 3773 Poster Board III-709 Introduction The tumor suppressor protein p53 induces cell cycle arrest and/or apoptosis in response to various forms of cellular stress, through transcriptional regulation of a large number of down stream target genes. p53 is frequently mutated in cancer, and cancer cells carrying defects in the p53 protein are often more resistant to conventional chemotherapy. Thus, restoration of the wild type function to mutant p53 appears to be a new attractive strategy for cancer therapy. APR-246 is a novel small molecule quinuclidinone compound that has been shown to reactivate non-functional p53 and induce apoptosis. Although the exact molecular mechanism remains to be determined, recent results suggest that an active metabolite of APR-246 alkylates thiol groups in the core domain of p53, which promotes correct folding of p53 and induces apoptosis (Lambert et al., Cancer Cell 15, 2009). Currently, APR-246 is in Phase I/IIa clinical trials for hematological malignancies and prostate cancer. In the present abstract results from in vitro, ex vivo and in vivo preclinical studies with APR-246 are presented. Results The lead compound of APR-246, PRIMA-1 (p53 reactivation and induction of massive apoptosis), was originally identified by a cellular screening of the NCI library for low molecular weight compounds (Bykov et al., Nat. Med., 8, 2002). Further development and optimization of PRIMA-1 led to the discovery of the structural analog APR-246 (PRIMA-1MET), with improved drug like and preclinical characteristics. In in vitro experiments APR-246 reduced cell viability (WST-1 assay) in a large number of human cancer cell lines with various p53 status, including several leukemia (CCRF-CEM, CEM/VM-1, KBM3), lymphoma (U-937 GTP, U-937-vcr), and myeloma (RPMI 8226/S, 8226/dox40, 8226/LR5) cell lines, as well as many solid cancer cell lines, including osteosarcoma (SaOS-2, SaOS-2-His273,U-2OS), prostate (PC3, PC3-His175, 22Rv1), breast (BT474, MCF-7, MDA-MB-231), lung (H1299, H1299-His175) and colon cancer (HT-29). In human osteosarcoma cell lines APR-246 reduced cell viability and induced apoptosis (FLICA caspase assay) in a concentration dependent manner being more potent in the p53 mutant (SaOS-2-His273) than in the parental p53 null (SaOS-2) cells. The IC50 values (WST-1 assay) were 14 ± 3 and 27 ± 5 μM, respectively (n=35). In in vivo subcutaneous xenograft studies in SCID (severe combined immunodeficiency) mice APR-246 reduced growth of p53 mutant SaOS-2-His273 cells in a dose-dependent manner, when injected i.v. twice daily with 20 -100 mg/kg (64 – 76% inhibition). An in vivo anticancer effect of APR-246 was also observed in hollow-fiber test with NMRI mice using the acute myeloid leukemia (AML) cell line MV-4-11. An ex vivo cytotoxic effect of APR-246 and/or its lead compound PRIMA-1 has also been shown in primary cells from AML and CLL (chronic lymphocytic leukemia) patients, harbouring both hemizygously deleted p53 as well as normal karyotype (Nahi et al., Br. J. Haematol., 127, 2004; Nahi et al., Br. J. Haematol., 132, 2005; Jonsson-Videsater et al., abstract at this meeting). APR-246 was also tested in a FMCA (fluorometric microculture assay) test using normal healthy lymphocytes (PBMC) and cancer lymphocytes (CLL). It was 4-8 fold more potent in killing cancer cells than normal cells, indicating a favorable therapeutic index. This is in contrast to conventional cytostatics that often show negative ratio in this test. Furthermore, when tested in a well-defined panel of 10 human cancer cell lines consisting of both hematological and solid cancer cell lines, the cytotoxicity profile/activity pattern of APR-246 differed from common chemotherapeutic drugs (correlation coefficient less than 0.4), suggesting a different mechanism of action. Conclusion In relevant in vitro, in vivo and ex vivo cancer models, APR-246 showed unique pharmacological properties in comparison with conventional cytostatics, by being effective also in cancer cells with p53 mutations and by demonstrating tumor specificity. Moreover, in experimental safety/toxicology models required to start clinical trials, APR-246 was non toxic at the predicted therapeutic plasma concentrations. Thus, APR-246 appears to be a promising novel anticancer compound that may specifically target cancer cells in patients with genetic abnormality associated with poor prognosis. Disclosures: Mohell: Aprea AB: Employment. Liljebris:Aprea AB: Employment. Alfredsson:Aprea AB: Employment. Lindman:Aprea AB: Employment. Uustalu:Aprea AB: Employment. Wiman:Aprea AB: Co-founder, shareholder, and member of the board. Uhlin:Aprea AB: Employment.

Anti-EpCAM XmAb antibodies with improved cytotoxicity

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12506-12506 ◽  
Author(s):  
O. Vafa ◽  
S. Kharki ◽  
J. Vielmetter ◽  
A. Chamberlain ◽  
P. Hammond ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Clinical Efficacy ◽  
Cancer Cell Lines ◽  
In Vitro Cytotoxicity ◽  
Binding Assays ◽  
Multiple Cancer ◽  
Effector Cells ◽  
Dependent Cell

12506 Background: The epithelial cell adhesion molecule (EpCAM), also known as epithelial protein 2 (EGP-2) or 17–1A antigen, is a trans-membrane protein expressed on the surfaces of most carcinomas, including those of pancreatic, colorectal, prostate, breast, kidney, lung, and ovarian origins. Moderate affinity antibodies (Abs) such as 17–1A (Kd ∼ 10−7 nM) have been safe in humans albeit with limited clinical efficacy. Attempts to improve clinical efficacy by enhancing antigen affinity (Kd ∼ 10−9 nM) have led to serious clinical toxicity, including pancreatitis. These observations raise the question of whether a moderate affinity Ab with enhanced effector function will be both safe and clinically efficacious. Methods: We applied our proprietary XmAb™ technologies to humanize the 17–1A variable domain and engineer a human IgG1 Fc domain to increase affinity for the activating receptor FcγRIIIa. Ab binding to Ep-CAM or to Fc receptors was tested with Biacore and/or AlphaScreen binding assays. In vitro cytotoxic activity against representative cancer cell lines was measured with Antibody Dependent Cell-mediated Cytotoxicity (ADCC) assays, using human PBMC as effector cells. Results: Humanized anti-EpCAM Abs have affinity for EpCAM similar to the parent 17–1A. Affinity for the activating FcγRIIIa was increased 100-fold relative to a control Ab with an IgG1 Fc domain. As expected, these Abs exhibit dramatically enhanced ADCC against multiple cancer cell lines relative to 17–1A and IgG1 control Abs. Despite their moderate affinity for EpCAM, these novel Abs have in vitro cytotoxicity comparable to the high affinity Ab ING-1. CDC activities of these Abs were similar to chimeric 17–1A. Conclusions: We have demonstrated that antibodies with moderate affinity for EpCAM and increased FcγRIIIa affinity exhibit superior cancer cell killing via an ADCC mechanism. The humanized nature and the increased cytotoxicity of anti-EpCAM XmAb™ antibodies make them promising candidates for clinical development of a novel pan-carcinoma Ab that is superior to 17–1A. [Table: see text]

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