scholarly journals Probing the Anticancer Action of Novel Ferrocene Analogues of MNK Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2126 ◽  
Author(s):  
Supojjanee Sansook ◽  
Ella Lineham ◽  
Storm Hassell-Hart ◽  
Graham J. Tizzard ◽  
Simon J. Coles ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitor ◽  
Leukemia Cell ◽  
Response Curves ◽  
Anticancer Effects ◽  
Leukemia Cell Lines ◽  
Ic50 Values ◽  
Compound Screening ◽  
Unique Shape

Two novel ferrocene-containing compounds based upon a known MNK1/2 kinase (MAPK-interacting kinase) inhibitor have been synthesized. The compounds were designed to use the unique shape of ferrocene to exploit a large hydrophobic pocket in MNK1/2 that is only partially occupied by the original compound. Screening of the ferrocene analogues showed that both exhibited potent anticancer effects in several breast cancer and AML (acute myeloid leukemia) cell lines, despite a loss of MNK potency. The most potent ferrocene-based compound 5 was further analysed in vitro in MDA-MB-231 (triple negative breast cancer cells). Dose–response curves of compound 5 for 2D assay and 3D assay generated IC50 values (half maximal inhibitory concentration) of 0.55 µM and 1.25 µM, respectively.

scholarly journals In Vitro Anticancer Activity and Mechanism of Action of an Aziridinyl Galactopyranoside

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 41
Author(s):  
Estefanía Burgos-Morón ◽  
Nuria Pastor ◽  
Manuel Luis Orta ◽  
Julio José Jiménez-Alonso ◽  
Carlos Palo-Nieto ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Excision Repair ◽  
Leukemia Cell ◽  
Normal Cells ◽  
Anticancer Effects ◽  
Leukemia Cell Lines ◽  
Bulky Dna Adducts ◽  
Inhibition Of Glycolysis

We recently screened a series of new aziridines β-D-galactopyranoside derivatives for selective anticancer activity and identified 2-methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-β-D-galactopyranoside (AzGalp) as the most promising compound. In this article, we explore the possible mechanisms involved in the cytotoxicity of this aziridine and evaluate its selective anticancer activity using cancer cells and normal cells from a variety of tissues. Our data show that AzGalp induces DNA damage (comet assay). Cells deficient in the nucleotide excision repair (NER) pathway were hypersensitive to the cytotoxicity of this compound. These results suggest that AzGalp induces bulky DNA adducts, and that cancer cells lacking a functional NER pathway may be particularly vulnerable to the anticancer effects of this aziridine. Several experiments revealed that neither the generation of oxidative stress nor the inhibition of glycolysis played a significant role in the cytotoxicity of AzGalp. Combinations of AzGalp with oxaliplatin or 5-fluorouracil slightly improved the ability of both anticancer drugs to selectively kill cancer cells. AzGalp also showed selective cytotoxicity against a panel of malignant cells versus normal cells; the highest selectivity was observed for two acute promyelocytic leukemia cell lines. Additional preclinical studies are necessary to evaluate the anticancer potential of AzGalp.

scholarly journals In Vitro Anticancer Activity and Mechanism of Action of an Aziridinyl Galactopyranoside

2018 ◽  
Author(s):  
Estefanía Burgos-Morón ◽  
Nuria Pastor ◽  
Manuel Luis Orta ◽  
Julio José Jiménez-Alonso ◽  
Carlos Palo-Nieto ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Excision Repair ◽  
Leukemia Cell ◽  
Normal Cells ◽  
Anticancer Effects ◽  
Leukemia Cell Lines ◽  
Bulky Dna Adducts ◽  
Inhibition Of Glycolysis

We recently screened a series of new aziridines β-D-galactopyranoside derivatives for selective anticancer activity and identified 2-methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-β-D-galactopyranoside (AzGalp) as the most promising compound. In this article, we explore possible mechanisms involved in the cytotoxicity of this aziridine and evaluate its selective anticancer activity using cancer cells and normal cells from a variety of tissues. Our data show that AzGalp induces DNA damage (detected with the comet assay). Cells deficient in the DNA repair pathway nucleotide excision repair (NER) were hypersensitive to the cytotoxicity of this compound. These results suggest that AzGalp induces bulky DNA adducts, and that cancer cells lacking a functional NER pathway may be particularly vulnerable to the anticancer effects of this aziridine. Several experiments revealed that neither the generation of oxidative stress nor the inhibition of glycolysis played a significant role in the cytotoxicity of AzGalp. The combinations of AzGalp with either oxaliplatin or 5-fluorouracil slightly improved the ability of both anticancer drugs to selectively kill cancer cells. AzGalp also displayed selective cytotoxicity against a panel of malignant cells versus normal cells; the highest selectivity was observed for two acute promyelocytic leukemia cell lines. Additional preclinical studies are necessary to evaluate the anticancer potential of AzGalp.

Coumarin-Fatty Acid Conjugates as Potential ERα/AKT-1 Antagonists for ER Positive Breast Cancer

2020 ◽  
Vol 20 (4) ◽  
pp. 437-449
Author(s):  
Jubie Selvaraj ◽  
Jameera B.A. John ◽  
Nanjan M. Joghee ◽  
Justin Antony ◽  
Ashish Wadhwani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Fatty Acid ◽  
Binding Assay ◽  
Uterine Cancer ◽  
Design Development ◽  
Structure Based Drug Design ◽  
Ic50 Values ◽  
Cancer Activity

Background: : Current drugs used for the treatment of hormone-dependent breast cancer function as anti-estrogens in the breast, in addition to Estrogen Receptor (ER) agonists in the uterus, thus elevate a woman’s risk of developing uterine cancer. This is due to the lack of selective binding and partial agonistic effect of these drugs towards estrogen receptors. In recent years, therefore, researchers have turned their attention towards antiestrogens devoid of these agonist properties and thus have a mechanism of action different from the existing drugs. Objective:: In this context, we report here the design, development and in vitro evaluation of some novel pharmacophores containing coumarin and fatty acid scaffolds for their anti-breast cancer activity. Methods: : A library of coumarin-fatty acid conjugates was designed using structure-based drug design approach. The conjugates which have shown good in silico results were then synthesized, characterized and evaluated for their anti-breast cancer activity by MTT assay, Apoptotic assay, Cell proliferation assay, Estrogen binding assay and Gene expression study. Results: Out of the fifteen compounds screened, two compounds, SAC-2 and LNAC-2, showed good activity with IC50 values 22µg/ml, 25μg/ml, respectively. These compounds suppressed the proliferation of ER overexpressed MCF-7 cells, increased ERα degradation and hence inactivate the ERα pathway. ER binding assay and gene expression RT-PCR study reveal that SAC-2 downregulated the expression of ERα receptor and AKT-1 gene. Conclusion:: Compound SAC-2 is a good antagonist to ER and hence has a potential for treating breast cancer and other cancers where AKT plays an important role.

scholarly journals Selective Targeting of Breast Cancer by Tafuramycin a Using SMA-Nanoassemblies

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3532
Author(s):  
Ibrahim M. El-Deeb ◽  
Valeria Pittala ◽  
Diab Eltayeb ◽  
Khaled Greish
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptors ◽  
In Vivo Studies ◽  
Chemotherapy Agent ◽  
Anticancer Effects ◽  
Tumor Tissues ◽  
Potential Strategy ◽  
Tumor Accumulation

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumors that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. The mainstay of treatment remains chemotherapy, but the therapeutic outcome remains inadequate. This paper investigates the potential of a duocarmycin derivative, tafuramycin A (TFA), as a new and more effective chemotherapy agent in TNBC treatment. To this extent, we optimized the chemical synthesis of TFA, and we encapsulated TFA in a micellar system to reduce side effects and increase tumor accumulation. In vitro and in vivo studies suggest that both TFA and SMA–TFA possess high anticancer effects in TNBC models. Finally, the encapsulation of TFA offered a preferential avenue to tumor accumulation by increasing its concentration at the tumor tissues by around four times in comparison with the free drug. Overall, the results provide a new potential strategy useful for TNBC treatment.

Leukemia cell lines: In vitro models for the study of acute promyelocytic leukemia

1995 ◽  
Vol 19 (10) ◽  
pp. 681-691 ◽  
Author(s):  
H.G. Drexler ◽  
H. Quentmeier ◽  
R.A.F. MacLeod ◽  
C.C. Uphoff ◽  
Z.-B. Hu
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Cell Lines ◽  
Leukemia Cell ◽  
In Vitro Models ◽  
Promyelocytic Leukemia ◽  
Leukemia Cell Lines

scholarly journals A Nitrocarbazole as a New Microtubule-Targeting Agent in Breast Cancer Treatment

2021 ◽  
Vol 11 (19) ◽  
pp. 9139
Author(s):  
Maria Stefania Sinicropi ◽  
Cinzia Tavani ◽  
Camillo Rosano ◽  
Jessica Ceramella ◽  
Domenico Iacopetta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Anticancer Activity ◽  
Breast Cancer Cell Lines ◽  
Cellular Functions ◽  
Anticancer Properties ◽  
Cycle Arrest ◽  
In Silico Studies ◽  
Ic50 Values ◽  
Mcf 7

Breast cancer is still considered a high-incidence disease, and numerous are the research efforts for the development of new useful and effective therapies. Among anticancer drugs, carbazole compounds are largely studied for their anticancer properties and their ability to interfere with specific targets, such as microtubule components. The latter are involved in vital cellular functions, and the perturbation of their dynamics leads to cell cycle arrest and subsequent apoptosis. In this context, we report the anticancer activity of a series of carbazole analogues 1–8. Among them, 2-nitrocarbazole 1 exhibited the best cytotoxic profile, showing good anticancer activity against two breast cancer cell lines, namely MCF-7 and MDA-MB-231, with IC50 values of 7 ± 1.0 and 11.6 ± 0.8 μM, respectively. Furthermore, compound 1 did not interfere with the growth of the normal cell line MCF-10A, contrarily to Ellipticine, a well-known carbazole derivative used as a reference molecule. Finally, in vitro immunofluorescence analysis and in silico studies allowed us to demonstrate the ability of compound 1 to interfere with tubulin organization, similarly to vinblastine: a feature that results in triggering MCF-7 cell death by apoptosis, as demonstrated using a TUNEL assay.

scholarly journals Hydrogel Tissue Construct-Based High-Content Compound Screening

2010 ◽  
Vol 16 (1) ◽  
pp. 120-128 ◽  
Author(s):  
Vy Lam ◽  
Tetsuro Wakatsuki
Keyword(s):  
Kinase Inhibitor ◽  
Physiological Mechanism ◽  
Rho Kinase ◽  
Assay System ◽  
Physiological Status ◽  
Multiple Parameters ◽  
Compound Screening ◽  
Tissue Construct

Current pharmaceutical compound screening systems rely on cell-based assays to identify therapeutic candidates and potential toxicities. However, cells grown on 2D substrata or in suspension do not exhibit the mechanical or physiological properties of cells in vivo. To address this limitation, the authors developed an in vitro, high-throughput, 3D hydrogel tissue construct (HTC)–based assay system to quantify cell and tissue mechanical properties and multiple parameters of physiology. HTC mechanics was quantified using an automated device, and physiological status was assessed using spectroscopy-based indicators that were read on microplate readers. To demonstrate the application of this system, the authors screened 4 test compounds—rotenone (ROT), cytochalasin D (CD), 2,4-dinitrophenol (DNP), and Rho kinase inhibitor (H-1152)—for their ability to modulate HTC contractility without affecting actin integrity, mitochondrial membrane potential (MMP), or viability. All 4 compounds dose-dependently reduced HTC contractility. However, ROT was toxic, DNP dissipated MMP, and CD reduced both intracellular F-actin and viability. H-1152 was found to be the best candidate compound since it reduced HTC contractility with minimal side effects. The authors propose that their HTC-based assay system can be used to screen for compounds that modulate HTC contractility and assess the underlying physiological mechanism(s) of compound activity and toxicity.

scholarly journals Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4454
Author(s):  
Damiano Cirri ◽  
Tanja Schirmeister ◽  
Ean-Jeong Seo ◽  
Thomas Efferth ◽  
Lara Massai ◽  
...  
Keyword(s):  
Leukemia Cell ◽  
Ubiquitin Proteasome System ◽  
Multidrug Resistant ◽  
Leukemia Cells ◽  
Initial Structure ◽  
Metal Compounds ◽  
Drug Candidates ◽  
Leukemia Cell Lines ◽  
Ic50 Values ◽  
Ubiquitin Proteasome

A group of triethylphosphine gold(I) and silver(I) complexes, structurally related to auranofin, were prepared and investigated as potential anticancer drug candidates. The antiproliferative properties of these metal compounds were assessed against two leukemia cell lines, i.e., CCRF-CEM and its multidrug-resistant counterpart, CEM/ADR5000. Interestingly, potent cytotoxic effects were disclosed for both series of compounds against leukemia cells, with IC50 values generally falling in the low-micromolar range, the gold derivatives being on the whole more effective than the silver analogues. Some initial structure-function relationships were drawn. Subsequently, the ability of the study compounds to inhibit the three main catalytic activities of the proteasome was investigated. Different patterns of enzyme inhibition emerged for the various metal complexes. Notably, gold compounds were able to inhibit effectively both the trypsin-like and chymotrypsin-like proteasome activities, being less effective toward the caspase-like catalytic activity. In most cases, a significant selectivity of the study compounds toward the proteasome proteolytic activities was detected when compared to other proteases. The implications of the obtained results are discussed.

scholarly journals Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 519 ◽  
Author(s):  
Ahmed Dhahir Latif ◽  
Tamás Jernei ◽  
Ana Podolski-Renić ◽  
Ching-Ying Kuo ◽  
Máté Vágvölgyi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mitochondrial Membrane ◽  
Redox Balance ◽  
Breast Cancer Cell Lines ◽  
Antitumor Action ◽  
Hybrid Compounds ◽  
Mitochondrial Membrane Depolarization ◽  
Ic50 Values ◽  
Novel Strategy

Hybrid compounds combine fragments with complementary targets to achieve a common pharmacological goal. This approach represents an increasingly popular strategy for drug discovery. In this work, we aimed to design antitumor hybrid compounds based on an inhibitor of ataxia-telangiectasia and Rad3-related protein (ATR)-dependent signaling, protoapigenone, and a pro-oxidant ferrocene or chalcone fragment. Four new triazole-coupled hybrids were prepared. The compounds were cytotoxic against human breast cancer cell lines in vitro, showing IC50 values in the sub-micromolar range. The nature of interactions between relevant fragments of the hybrids was evaluated by the Chou–Talalay method. Experimental combination treatment with the fragments showed additive effects or slight/moderate synergism, while strong synergism was observed when the fragments were virtually combined into their hybrids, suggesting a relevant pharmacological benefit of the coupling. All hybrids were strong inhibitors of the ATR-mediated activation of Chk1, and they interfered with the redox balance of the cells leading to mitochondrial membrane depolarization. Additionally, they induced late apoptosis and primary necrosis in MDA-MB-231 and MCF-7 breast cancer cells, respectively. Our results demonstrate that coupling the ATR-dependent signaling inhibitor protoflavone with a pro-oxidant chalcone dramatically increases the antitumor activity compared with either fragment alone. Such compounds may offer an attractive novel strategy for the treatment of various cancers.

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