Mechanisms of cytotoxic action of a series of directionally synthesized heterocyclic hydroxamic acids

2020 ◽  
Vol 66 (4) ◽  
pp. 332-338
Author(s):  
M.E. Neganova ◽  
Yu.R. Aleksandrova ◽  
S.A. Pukhov ◽  
S.G. Klochkov ◽  
V.N. Osipov
Keyword(s):  
Histone Deacetylases ◽  
Cytotoxic Effect ◽  
Human Lung ◽  
Hydroxamic Acids ◽  
Breast Adenocarcinoma ◽  
Cytotoxic Action ◽  
Oxygen Species ◽  
Cyclic Hydroxamic Acids ◽  
Human Lung Carcinoma ◽  
Mcf 7

Cyclic hydroxamic acids based on quinazoline-4(3H)-one and dihydroquinazoline-4(1H)-one have been synthesized. The antioxidant and iron-chelating properties of these compounds, their effect on the activity of the histone deacetylase enzyme, and their cytotoxic effect on cells of various tumor lines have been investigated. We have identified two compounds-hits, which exhibit the multipharmacological type of the antineoplastic activity. Their cytotoxic effect on cells of human lung carcinoma A549 and breast adenocarcinoma MCF-7 is obviously associated with their ability to modulate the level of reactive oxygen species and to chelate Fe(II) ions, as well as to inhibit the metalloenzymes, histone deacetylases, involved in the epigenetic regulation of tumor genesis. Thus, the synthesized hydroxamic acids may be considered as a promising basis for creating potential oncolytics.

Chemosensitizing Activity of Histone Deacetylases Inhibitory Cyclic Hydroxamic Acids for Combination Chemotherapy of Lymphatic Leukemia

2018 ◽  
Vol 18 (4) ◽  
pp. 365-371 ◽  
Author(s):  
Denis V. Mishchenko ◽  
Margarita E. Neganova ◽  
Elena N. Klimanova ◽  
Tatyana E. Sashenkova ◽  
Sergey G. Klochkov ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Acute Toxicity ◽  
Histone Deacetylases ◽  
Hydroxamic Acids ◽  
Water Soluble ◽  
Male Rat ◽  
Hybrid Male ◽  
Cyclic Hydroxamic Acids

Background: Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis. Objective: The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents. Method: Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study. Results: Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine < Alanine < Valine < Leucine < Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a-e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro-tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg. Conclusion: It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c.

scholarly journals Mycoplasma pneumoniae Infection Induces Reactive Oxygen Species and DNA Damage in A549 Human Lung Carcinoma Cells

2008 ◽  
Vol 76 (10) ◽  
pp. 4405-4413 ◽  
Author(s):  
Gongping Sun ◽  
Xuefeng Xu ◽  
Yingshuo Wang ◽  
Xiaoyun Shen ◽  
Zhimin Chen ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Mycoplasma Pneumoniae ◽  
Lung Carcinoma ◽  
Human Lung ◽  
Reactive Oxygen ◽  
Carcinoma Cells ◽  
Oxygen Species ◽  
Lung Carcinoma Cells ◽  
Human Lung Carcinoma

ABSTRACT Mycoplasma pneumoniae is a frequent cause of community-acquired bacterial respiratory infections in children and adults. In the present study, using a proteomic approach, we studied the effects of M. pneumoniae infection on the protein expression profile of A549 human lung carcinoma cells. M. pneumoniae infection induced changes in the expression of cellular proteins, in particular a group of proteins involved in the oxidative stress response, such as glucose-6-phosphate 1-dehydrogenase, NADH dehydrogenase (ubiquinone) Fe-S protein 2, and ubiquinol-cytochrome c reductase complex core protein I mitochondrial precursor. The oxidative status of M. pneumoniae-infected cells was evaluated, and the results revealed that M. pneumoniae infection indeed caused generation of reactive oxygen species (ROS). It was further shown that M. pneumoniae infection also induced DNA double-strand breaks, as demonstrated by the formation of γH2AX foci. On the other hand, an ROS scavenger, N-acetylcysteine, could inhibit the ROS generation, as well as decrease γH2AX focus formation. This is the first report showing that M. pneumoniae infection can directly induce DNA damage, at least partially, through the generation of ROS, and thus this report strengthens the powerful application of proteomics in the study of the pathogenesis of M. pneumoniae.

scholarly journals An Investigation on Cytotoxicity Effect of Putrescine-Sulphur Analogues on Breast Cancer (Mcf-7), Human Lung Adenocarcinoma (A549) and Colorectal Cancer (Hct-8) Cell Lines

2017 ◽  
Vol 16 (1) ◽  
Author(s):  
Norsuhana Halim ◽  
Radiah Abdul Ghani ◽  
Adzly Hairee Sahabudin ◽  
Fiona How Ni Fong
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Cells ◽  
Cell Lines ◽  
Human Lung ◽  
Breast Adenocarcinoma ◽  
Normal Cells ◽  
Human Lung Adenocarcinoma ◽  
Adenocarcinoma Cells ◽  
Specific Cancer ◽  
Mcf 7

Introduction: Cancer is one of the global health problems that has a detrimental effect to a person's life. However, chemotherapeutic agents success are subject to the side effects due to lack of specificity in the drug delivery system to cancer cells and an increase risk of systemic toxicity to the normal cells. Polyamine transport system (PTS) is one of the potential pathways for transporting anticancer agent into specific cancer cells. This is due to the upregulation of PTS in cancer cells compared to normal cells for the proliferation activity. The aim of this study was to investigate the cytotoxicity effect of putrescine-sulphur analogues type 1 (PSA-1) and type 2 (PSA-2) on human lung adenocarcinoma cells (A549), human colorectal adenocarcinoma cells (HCT-8) and human breast adenocarcinoma cell (MCF-7). Materials and method: The cytotoxicity effect of newly synthesized PSA-1 and PSA-2 were evaluated on selected cancer cells; MCF-7, A549 and HCT-8 cell lines. The halfmaximal inhibitory concentration (IC50) obtained from tetrazolium bromide (MTT) assay was derived from the dose-response graph for all cell lines. Results: PSA-2 elicited cytotoxicity effect, eventhough the IC50 values were not potent with IC50 of 5.4 mM, 5.2 mM and 7.0 mM for MCF-7/48h, A549/48h and HCT-8/48h, respectively. The PSA-1 compound exhibited cytotoxicity effect in all cell lines, however, the compound failed to induce anti-proliferation at the concentration of 3 mM and above. The cytotoxicity of PSA-2 compound against MCF-7 cell lines showed higher potency compared to A549 and HCT-8 cell lines. Conclusion: It was suggested that PSA-2 compound was able to exert cytotoxicity effect against selected cancer cells, in low potency and is deemed for further investigation to increase its effectiveness against specific cancer cells.

scholarly journals Comparison of the Effects of Resveratrol and Its Derivatives on the Radiation Response of MCF-7 Breast Cancer Cells

2021 ◽  
Vol 22 (17) ◽  
pp. 9511
Author(s):  
Dominika Komorowska ◽  
Agnieszka Gajewska ◽  
Paweł Hikisz ◽  
Grzegorz Bartosz ◽  
Aleksandra Rodacka
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cytotoxic Effect ◽  
Breast Cancer Treatment ◽  
Radiation Response ◽  
Oxygen Species ◽  
Stilbene Derivatives ◽  
Apoptotic Genes ◽  
Mcf 7

Radiotherapy is among the most important methods for breast cancer treatment. However, this method’s effectiveness is limited by radioresistance. The aim of this study was to investigate whether the stilbene derivatives piceid, resveratrol, and piceatannol have a radiosensitising effect on breast cancer cells (MCF-7). The conducted research enabled us to determine which of the tested compounds has the greatest potential in sensitising cells to ionising radiation (IR). Among the stilbene derivatives, resveratrol significantly increased the effect of IR. Resveratrol and IR used in combination had a higher cytotoxic effect on MCF-7 cells than using piceatannol, piceid, or radiation alone. This was due to a significant decrease in the activity of antioxidant enzymes, which resulted in the accumulation of formed reactive oxygen species (ROS). The effect of resveratrol and IR enhanced the expression of apoptotic genes, such as Bax, p53, and caspase 8, leading to apoptosis.

scholarly journals Polyisoprenylated Acylphloroglucinols from Garcinia nervosa

2018 ◽  
Vol 13 (3) ◽  
pp. 1934578X1801300 ◽  
Author(s):  
Alfarius Eko Nugroho ◽  
Hitomi Nakamura ◽  
Daisuke Inoue ◽  
Yusuke Hirasawa ◽  
Chin Piow Wong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cytotoxic Activity ◽  
Spectroscopic Data ◽  
Human Lung ◽  
Carcinoma Cells ◽  
Breast Adenocarcinoma ◽  
Human Breast ◽  
Human Breast Adenocarcinoma ◽  
Human Hepatocellular Carcinoma Cells ◽  
Mcf 7

Two new polyisoprenylated acylphloroglucinols, 7- epi-isoxanthochymol and 7- epi-cycloxanthochymol (1 – 2), were isolated from the barks of Garcinia nervosa together with their 7-epimers isoxanthochymol (3) and cycloxanthochymol (4). Their structures were determined on the basis of NMR spectroscopic data. The cytotoxic activity of the isolated compounds against HL-60, MCF-7 (human breast adenocarcinoma), A549 (human lung adenocarcinoma) and HepG2 (human hepatocellular carcinoma) cells were evaluated, and all compounds showed cytotoxic activity against all cell lines.

Therapeutically Potential of Medicago sativa Extracts. Chemical and in vitro assessments

2018 ◽  
Vol 69 (1) ◽  
pp. 121-124
Author(s):  
Iulia Pinzaru ◽  
Alina Heghes ◽  
Daniela Marti ◽  
Cristina Dehelean ◽  
Dorina Coricovac ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Medicago Sativa ◽  
Cytotoxic Effect ◽  
Human Lung ◽  
Polar Solvent ◽  
Total Phenols ◽  
Tumor Cell Lines ◽  
Human Breast ◽  
Human Lung Carcinoma

The present study was aimed to evaluate total phenols, flavonoid and flavonols content and to assess relative cytotoxicity of Medicago sativa hydro-alcoholic and alcoholic leaves and stems extracts on human lung carcinoma (A549) and human breast carcinoma (MDA-MB-231). All extracts tested have proven to be rich in hydroxylated compounds, larger amounts of phenolic compounds were found in extracts obtained using 70% ethanol, a proper polar solvent for this molecule types. Evaluation of antioxidant activity reveals values all most comparable with the ones of ascorbic acid. The extracts induced a cytotoxic effect on both tumor cell lines in a concentration-depend manner.

scholarly journals The Cytotoxicity Effect of Spermidine -Sulphur Analogues Type 1 (Ssa-1) And Type 2 (Ssa-2) against Human Lung Adenocarcinoma Cells (A549), Human Colorectal Adenocarcinoma Cells (Hct-8), and Human Breast Adenocarcinoma Cells (Mcf-7)

2017 ◽  
Vol 16 (1) ◽  
Author(s):  
Masnizahani binti Jamil ◽  
Radiah Abdul Ghani ◽  
Adzly Hairee Sahabudin ◽  
Fiona How Ni Fong
Keyword(s):  
Cell Lines ◽  
Colorectal Adenocarcinoma ◽  
Human Lung ◽  
Breast Adenocarcinoma ◽  
Human Breast ◽  
Adenocarcinoma Cells ◽  
Human Lung Adenocarcinoma Cells ◽  
Mcf 7

Introduction: Over accumulation of polyamines is one of the causes of cancer because polyamines could promote the cancer cells growth. Due to the lack of specificity and increased reports of side effects in the current cancer treatment, one of the strategies to overcome the challenges is by utilizing polyamines as vectors of known cytotoxic compounds to target the cancer cells. Therefore, this study was aimed to investigate the cytotoxicity effect of Spermidine Sulphur Analogues Type 1 and Type 2 (SSA-1 and SSA-2) against human lung adenocarcinoma cells (A549), human colorectal adenocarcinoma cells (HCT-8) and human breast adenocarcinoma cell (MCF-7).  Materials and method: The cytotoxicity studies of SSA-1 and SSA-2 against in vitro cells: A549, HCT-8, and MCF-7 were carried out by using MTT assay and the IC50 in each cell was determined.  Results: SSA-1 exhibited cytotoxicity effect in all selected cell lines with IC50 between 2.0 mM to 5.3 mM. While SSA-2 also exhibited cytotoxicity effect in all cell lines with IC50 between 0.8 mM to 5.0 mM.  Conclusion: SSA-1 and SSA-2 were cytotoxic against A549, HCT-8, and MCF-7. However, the cytotoxic effect was not potent against these cell lines as a higher concentration of compounds was needed to inhibit the cells growth. Hence, it is suggested that further study on the cytotoxicity effect of SSA-1 and SSA-2 in other cell lines should be conducted and the formulation of the analogues based on sulphur should be amended by conjugating it with selected metal.

Mechanisms of the Cytotoxic Action of Novel Cyclic Hydroxamic Acids

2020 ◽  
Vol 14 (4) ◽  
pp. 340-346
Author(s):  
M. E. Neganova ◽  
Yu. R. Aleksandrova ◽  
S. A. Pukhov ◽  
S. G. Klochkov ◽  
V. N. Osipov
Keyword(s):  
Hydroxamic Acids ◽  
Cytotoxic Action ◽  
Cyclic Hydroxamic Acids
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