scholarly journals Tuning the Polymorphism of the Anti-VEGF G-rich V7t1 Aptamer by Covalent Dimeric Constructs

2020 ◽  
Vol 21 (6) ◽  
pp. 1963 ◽  
Author(s):  
Claudia Riccardi ◽  
Domenica Musumeci ◽  
Chiara Platella ◽  
Rosa Gaglione ◽  
Angela Arciello ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
Breast Adenocarcinoma ◽  
Vascular Endothelial ◽  
Binding Ability ◽  
Biophysical Characterization ◽  
G Quadruplex ◽  
Biophysical Techniques ◽  
Endothelial Growth Factor ◽  
Thermal Stability Of ◽  
Mcf 7

In the optimization process of nucleic acid aptamers, increased affinity and/or activity are generally searched by exploring structural analogues of the lead compound. In many cases, promising results have been obtained by dimerization of the starting aptamer. Here we studied a focused set of covalent dimers of the G-quadruplex (G4) forming anti-Vascular Endothelial Growth Factor (VEGF) V7t1 aptamer with the aim of identifying derivatives with improved properties. In the design of these covalent dimers, connecting linkers of different chemical nature, maintaining the same polarity along the strand or inverting it, have been introduced. These dimeric aptamers have been investigated using several biophysical techniques to disclose the conformational behavior, molecularity and thermal stability of the structures formed in different buffers. This in-depth biophysical characterization revealed the formation of stable G4 structures, however in some cases accompanied by alternative tridimensional arrangements. When tested for their VEGF165 binding and antiproliferative activity in comparison with V7t1, these covalent dimers showed slightly lower binding ability to the target protein but similar if not slightly higher antiproliferative activity on human breast adenocarcinoma MCF-7 cells. These results provide useful information for the design of improved dimeric aptamers based on further optimization of the linker joining the two consecutive V7t1 sequences.

scholarly journals Toward G-Quadruplex-Based Anticancer Agents: Biophysical and Biological Studies of Novel AS1411 Derivatives

2020 ◽  
Vol 21 (20) ◽  
pp. 7781
Author(s):  
Anna M. Ogloblina ◽  
Nunzia Iaccarino ◽  
Domenica Capasso ◽  
Sonia Di Gaetano ◽  
Emanuele U. Garzarella ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
Topoisomerase I ◽  
Biological Effects ◽  
Structural Features ◽  
Breast Adenocarcinoma ◽  
Sequence Length ◽  
Biological Studies ◽  
G Quadruplex ◽  
Mcf 7

Certain G-quadruplex forming guanine-rich oligonucleotides (GROs), including AS1411, are endowed with cancer-selective antiproliferative activity. They are known to bind to nucleolin protein, resulting in the inhibition of nucleolin-mediated phenomena. However, multiple nucleolin-independent biological effects of GROs have also been reported, allowing them to be considered promising candidates for multi-targeted cancer therapy. Herein, with the aim of optimizing AS1411 structural features to find GROs with improved anticancer properties, we have studied a small library of AS1411 derivatives differing in the sequence length and base composition. The AS1411 derivatives were characterized by using circular dichroism and nuclear magnetic resonance spectroscopies and then investigated for their enzymatic resistance in serum and nuclear extract, as well as for their ability to bind nucleolin, inhibit topoisomerase I, and affect the viability of MCF-7 human breast adenocarcinoma cells. All derivatives showed higher thermal stability and inhibitory effect against topoisomerase I than AS1411. In addition, most of them showed an improved antiproliferative activity on MCF-7 cells compared to AS1411 despite a weaker binding to nucleolin. Our results support the hypothesis that the antiproliferative properties of GROs are due to multi-targeted effects.

Synthesis, Characterization and Antiproliferative Activity Assessment of a Novel 1H-5-mercapto-1,2,4 Triazole Derivative

2017 ◽  
Vol 68 (4) ◽  
pp. 745-747 ◽  
Author(s):  
Marius Mioc ◽  
Sorin Avram ◽  
Vasile Bercean ◽  
Mihaela Balan Porcarasu ◽  
Codruta Soica ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
Biological Activities ◽  
Cancer Cell Line ◽  
Vascular Endothelial ◽  
Triazole Derivative ◽  
Activity Assessment ◽  
Wide Range ◽  
Specific Receptors ◽  
Endothelial Growth Factor ◽  
Selection Of

Angiogenesis plays an important function in tumor proliferation, one of the main angiogenic promoters being the vascular endothelial growth factor (VEGF) which activates specific receptors, particularly VEGFR-2. Thus, VEGFR-2 has become an essential therapeutic target in the development of new antitumor drugs. 1,2,4-triazoles show a wide range of biological activities, including antitumor effect, which was documented by numerous reports. In the current study the selection of 5-mercapto-1,2,4-triazole structure (1H-3-styryl-5-benzylidenehydrazino-carbonyl-methylsulfanil-1,2,4-triazole, Tz3a.7) was conducted based on molecular docking that emphasized it as suitable ligand for VEGFR-2 and EGFR1 receptors. Compound Tz3a.7 was synthesized and physicochemically and biologically evaluated thus revealing a moderate antiproliferative activity against breast cancer cell line MDA-MB-231.

scholarly journals Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

2007 ◽  
Vol 196 (2) ◽  
pp. 399-412 ◽  
Author(s):  
Hélène Buteau-Lozano ◽  
Guillaume Velasco ◽  
Monique Cristofari ◽  
Patrick Balaguer ◽  
Martine Perrot-Applanat
Keyword(s):  
Breast Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Estrogen Receptor ◽  
Growth Factor ◽  
Breast Cancer Cells ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor ◽  
Dependent Mechanism ◽  
Mcf 7

Environmental chemicals may affect human health by disrupting endocrine function. Their possible role in the mammary gland and breast tumors is still unknown. Previous studies have demonstrated that vascular endothelial growth factor (VEGF), a key factor in angiogenesis and tumor progression, is an estrogen-regulated gene. We analyzed whether VEGF expression is regulated by different xenoestrogens in several breast cancer cells, MELN (derived from MCF-7) and MELP (derived from MDA-MB-231) and stably expressing estrogen receptor α (ERα); these cell lines stably express estrogen response element (β-globin)-luciferase. Genistein, bisphenol A (BPA), 4-(tert-octyl)phenol (OP), dieldrin, and several phthalates, including benzyl butyl phthalate (BBP) and di-ethyl-2-hexyle phthalate (DEHP), were first shown to be estrogenic. These compounds induced a dose-dependent increase of VEGF secretion in MELN and MCF-7 cells; maximal effect was observed at 1–10 μM non-cytotoxic concentrations and was inhibited by the antiestrogen ICI 182 780. VEGF increase was not observed in ERα-negative MDA-MB-231 cells. Most substances increased VEGF transcript levels in MELN cells. In contrast, γ-hexachlorocyclohexane, vinclozolin, and the phthalates (mono-n-butyl ester phthalic acid, di-isononyle phthalate, and di-isodecyle phthalate) were ineffective on both VEGF secretion and estrogenic luciferase induction in these cell lines. Specific kinase inhibitors PD98059, SB203580, or LY294002 suppressed the xenoestrogen-induced VEGF response, suggesting activation of MEK, p38 kinase, and phosphatidylinositol-3-kinase pathways. Our in vitro results show for the first time that genistein and xenoestrogens (BPA, OP, dieldrin, BBP, and DEHP at high concentrations) up-regulate VEGF expression in MELN cells by an ER-dependent mechanism. Since VEGF increases capillary permeability and breast tumor angiogenesis in vivo, the physiological relevance of these findings is discussed.

scholarly journals Modulation of Tamoxifen Cytotoxicity by Caffeic Acid Phenethyl Ester in MCF-7 Breast Cancer Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Tarek K. Motawi ◽  
Samy A. Abdelazim ◽  
Hebatallah A. Darwish ◽  
Eman M. Elbaz ◽  
Samia A. Shouman
Keyword(s):  
Breast Cancer ◽  
Caffeic Acid ◽  
Caffeic Acid Phenethyl Ester ◽  
Term Therapy ◽  
Vascular Endothelial ◽  
Cytotoxic Effects ◽  
Long Term Therapy ◽  
Endothelial Growth Factor ◽  
Mcf 7

Although Tamoxifen (TAM) is one of the most widely used drugs in managing breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE) is a polyphenolic compound present in many medicinal plants and in propolis. The present study examined the effect of CAPE on TAM cytotoxicity in MCF-7 cells. MCF-7 cells were treated with different concentrations of TAM and/or CAPE for 48 h. This novel combination exerted synergistic cytotoxic effects against MCF-7 cells via induction of apoptotic machinery with activation of caspases and DNA fragmentation, along with downregulation of Bcl-2 and Beclin 1 expression levels. However, the mammalian microtubule-associated protein light chain LC 3-II level was unchanged. Vascular endothelial growth factor level was also decreased, whereas levels of glutathione and nitric oxide were increased. In conclusion, CAPE augmented TAM cytotoxicity via multiple mechanisms, providing a novel therapeutic approach for breast cancer treatment that can overcome resistance and lower toxicity. This effect provides a rationale for further investigation of this combination.

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