Design, Synthesis and Biological Evaluation of Novel N-hydroxyheptanamides Incorporating 6-hydroxy-2-methylquinazolin-4(3H)-ones as Histone Deacetylase Inhibitors and Cytotoxic Agents

2019 ◽  
Vol 19 (12) ◽  
pp. 1543-1557
Author(s):  
Nguyen V. Minh ◽  
Nguyen T. Thanh ◽  
Hoang T. Lien ◽  
Dinh T.P. Anh ◽  
Ho D. Cuong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Discovery ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Cancer Cell ◽  
Hdac Inhibitors ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
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Background: Target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development worldwide, and Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as vorinostat and belinostat. Aims: This study aims at developing novel HDAC inhibitors bearing quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines. Methods: A series of novel N-hydroxyheptanamides incorporating 6-hydroxy-2 methylquinazolin-4(3H)-ones (14a-m) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2 (liver cancer), MCF-7 (breast cancer) and SKLu-1 (lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. ADME-T predictions for selected compounds were also performed to predict some important features contributing to the absorption profile of the present hydroxamic derivatives. Results: It was found that the N-hydroxyheptanamide 14i and 14j were the most potent, both in terms of HDAC inhibition and cytotoxicity. These compounds displayed up to 21-71-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in terms of cytotoxicity, and strong inhibition against the whole cell HDAC enzymes with IC50 values of 7.07-9.24μM. Docking experiments on HDAC2 isozyme using Autodock Vina showed all compounds bound to HDAC2 with relatively higher affinities (from -7.02 to -11.23 kcal/mol) compared to SAHA (-7.4 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward breast cancer cells (MCF-7) than liver (HepG2), and lung (SKLu-1) cancer cells.

Novel Conjugated Quinazolinone-Based Hydroxamic Acids: Design, Synthesis and Biological Evaluation

2020 ◽  
Vol 16 ◽  
Author(s):  
Tran Khac Vu ◽  
Nguyen Thi Thanh ◽  
Nguyen Van Minh ◽  
Nguyen Huong Linh ◽  
Nguyen Thi Phương Thao ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cell Lines ◽  
Cancer Cell ◽  
Hdac Inhibitors ◽  
Cancer Cell Lines ◽  
Hydroxamic Acids ◽  
Biological Evaluation ◽  
Hdac Inhibition ◽  
Ic50 Value ◽  
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Background: Target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development. Histone deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as vorinostat and belinostat. Aims: This study aims at developing novel HDAC inhibitors bearing conjugated quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines. Method: A series of novel N-hydroxyheptanamides incorporating conjugated 6-hydroxy-2 methylquinazolin-4(3H)- ones (15a-l) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2, MCF-7 and SKLu-1. Molecular simulations were finally performed to gain more insight into the structure-activity. relationships. Results: It was found that among novel conjugated quinazolinone-based hydroxamic acids synthesized, compounds 15a, 15c and 15f were the most potent, both in terms of HDAC inhibition and cytotoxicity. Especially, compound 15f displayed up to nearly 4-fold more potent than SAHA (vorinostat) in terms of cytotoxicity against MCF-7 cell line with IC50 value of 1.86 µM, and HDAC inhibition with IC50 value of 6.36 µM. Docking experiments on HDAC2 isozyme showed that these compounds bound to HDAC2 with binding affinities ranging from -10.08 to -14.93 kcal/mol compared to SAHA (-15.84 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward SKLu-1than MCF-7 and HepG-2. Conclusion: The resesrch results suggest that some hydroxamic acids could emerge for further evaluation and the results are well served as basics for further design of more potent HDAC inhibitors and antitumor agents.

scholarly journals WD-3 inhibits the proliferation of breast cancer cells by regulating the glycolytic pathway

2020 ◽  
Author(s):  
Xiaodan Zhu ◽  
Lu Zhao ◽  
Jianliang You ◽  
Yiqun Ni ◽  
Zhipeng Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Hexokinase 2 ◽  
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Number 3 Prescription (WD-3) is an herbal remedy used in traditional Chinese medicine that has been shown to improve the outcomes of patients with advanced colon and gastric cancers. This study aimed to investigate the effect of WD-3 on proliferation, glycolysis, and hexokinase 2 expression in breast cancer cells. Four breast cancer cell lines (MDA-MB-231, BT-549, MCF-7, and MCF-7/ADR-RES) were treated with different concentrations of WD-3 compared with blank control (phosphate-buffered saline). Each of the breast cancer cell lines was also divided into WD-3, paclitaxel, and blank control group. Cell proliferation and morphology were assessed by MTT assay, nuclear Hoechst 33258 staining, or immunofluorescence. Apoptosis was analyzed by flow cytometry. High performance liquid chromatography was used for measurement of ATP, ADP, and AMP. Hexokinase 2 expression was analyzed by Western blot and quantitative reverse transcription PCR. WD-3 inhibited proliferation and increased apoptosis in all four breast cancer cell lines, in a dose-dependent manner. ATP and EC (energy charge) were significantly decreased in WD-3-treated BT-549 and MDA-MB-231 cells. WD-3 significantly downregulated the protein and mRNA expression of hexokinase II in BT-549 cells, however, not in the other three breast cancer cell lines. Our findings indicate that WD-3 targets the glycolytic pathway in breast cancer cells to exert its antitumor activity.

Endocytosis of pro-cathepsin D into breast cancer cells is mostly independent of mannose-6-phosphate receptors

1998 ◽  
Vol 111 (17) ◽  
pp. 2539-2549 ◽  
Author(s):  
V. Laurent-Matha ◽  
M.R. Farnoud ◽  
A. Lucas ◽  
C. Rougeot ◽  
M. Garcia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cathepsin D ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Mannose 6 Phosphate ◽  
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Cathepsin D trafficking is altered in cancer cells, leading to increased secretion of the pro-enzyme, which can be reinternalized by the same cancer cells and by stromal cells. We studied pro-cathepsin D endocytosis in two human breast cancer cell lines (MDA-MB231, MCF-7) and in human normal fibroblasts. Pro-enzyme uptake was studied indirectly through immunofluorescence analysis of anti-pro-cathepsin D monoclonal antibodies internalized in living cells. Both cancer cell lines internalized the pro-cathepsin D-antibody complex into endosomal compartments in the presence of 10 mM mannose-6-phosphate. Non-malignant fibroblasts, which do not secrete pro-cathepsin D, only internalized anti-cathepsin D antibody when purified pro-cathepsin D was added and this endocytosis was totally inhibited by mannose-6-phosphate. Cathepsin D endocytosis in cancer cells was not mediated by lectins or another receptor binding the cathepsin profragment. It was not due to fluid endocytosis, since another protein pS2 secreted by MCF-7 was not endocytosed with its antibody in the same conditions. Double-immunofluorescence and confocal microscopy analyses revealed that antibodies specific to pro-cathepsin D (M2E8) and to the mannose-6-phosphate/IGFII receptor were co-internalized independently in non-permeabilized MDA-MB231 cells and MCF-7 cells, but not in fibroblasts. Moreover, when metabolically labelled pro-cathepsin D secreted by MCF-7 or MDA-MB231 cells was incubated with homologous or heterologous non-radioactive cells, the time-dependent uptake and maturation of the pro-enzyme into fibroblasts were totally inhibited by mannose-6-phosphate, whereas they were not in the two breast cancer cell lines. The percentage of mannose-6-phosphate-independent binding of radioactively labelled pro-cathepsin D to MDA-MB231 cells at 16 degrees C was higher (7–8%) at low pro-cathepsin D concentration than at high concentration (1.5%), indicating the presence of saturable binding site(s) at the cell surface that are different from the mannose-6-phosphate receptors. We conclude that, in contrast to fibroblasts, breast cancer cells can endocytose the secreted pro-cathepsin D by a cell surface receptor that is different from the mannose-6-phosphate receptors or other lectins. The nature of this alternative receptor and its significance in the action of secreted pro-cathepsin D remain to be elucidated.

Soluble Inflammatory Mediators Proteinase-3 and Neutrophil Elastase Are Targeted by PR1-Specific Immunotherapy After Cellular Uptake and Cross Presentation of PR1 Peptide by Breast Cancer Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2089-2089
Author(s):  
Gheath Alatrash ◽  
Elizabeth Mittendorf ◽  
Anna Sergeeva ◽  
Pariya Sukhumalchandra ◽  
Na Qiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Cross Presentation ◽  
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Abstract Abstract 2089 The human leukocyte antigen (HLA)-A2 restricted nonapeptide PR1 (VLQELNVTV) was shown to be immunogenic in leukemia. A phase I/II clinical trial has been initiated with PR1 peptide vaccine and to date has demonstrated clinical efficacy, including complete remission and immunologic responses in patients with acute (AML) and chronic (CML) myeloid leukemia, as well as myelodysplastic syndrome. PR1 is derived from the serine proteases proteinase-3 (P3) and neutrophil elastase (NE), which are normally found within neutrophil azurophil granules and are released into the inflammatory milieu. We have shown that P3 and NE are taken up and cross presented by antigen presenting cells and that their cross presentation elicits PR1 immunity. Because P3 and NE are present in breast cancer biopsies, we hypothesized that P3/NE may be taken up by breast cancer cells and cross presented to PR1-CTL. We recently demonstrated that the breast cancer cell lines MDA-MB-231, MDA-MB-453, MCF-7 and HER18 do not endogenously express NE and that NE is taken up by these cell lines. In this report, using PCR, western blot and flow cytometry, we show that P3 also is NOT endogenously expressed by the breast cancer cell lines MDA-MB-231, MDA-MB-453, MCF-7 or HER18. Using confocal microscopy, we demonstrate that P3 is taken up by these breast cancer cell lines within 10 minutes of pulsing and localizes to LAMP-2 containing lysosomal vesicles by 4 hours, suggesting its processing for presentation by (HLA)-I (i.e. HLA-A2). Using 8F4, the novel PR1-HLA-A2 monoclonal antibody, we show that PR1 is cross presented from P3 by 3 of 4 HLA-A2+ breast cancer cell lines (MDA-MB-231, MDA-MB-453-A2+, MCF-7), and from NE by 1 of 4 breast cancer cell lines (MDA-MB-231). Next, we studied whether PR1 presentation made cells susceptible to PR1-specific killing by PR1-CTL and the 8F4 monoclonal antibody. We show that following 12-hour pulsing of the MDA-MB-231 cell line with NE or P3, PR1 CTLs killed up to 31% and 38% of the NE- or P3-pulsed breast cancer cells respectively, vs. <1% of ovalbumin (ova)-pulsed MDA-MB-231cells. Additionally, in a complement mediated cytotoxicity assay using 8F4 antibody, pulsing of MDA-MB-231 cells with P3 led to 60% cytotoxicity (vs. 40% in ova-pulsed cells). In conclusion, this study shows that 1) PR1 is cross presented by breast cancer cells following uptake of soluble P3 and NE and 2) PR1 expression makes breast cancer a target of PR1-specific immunotherapy. If uptake of P3 or NE, present in the inflammatory milieu of other solid tumors, also leads to PR1 cross presentation, then PR1-based immunotherapy may be useful to treat other non-hematopoietic tumors. These results support a new paradigm linking inflammation and innate immunity to adaptive immune responses to cancer. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Role of WISP-2/CCN5 in the Maintenance of a Differentiated and Noninvasive Phenotype in Human Breast Cancer Cells

2007 ◽  
Vol 28 (3) ◽  
pp. 1114-1123 ◽  
Author(s):  
Asmaà Fritah ◽  
Cécile Saucier ◽  
Olivier De Wever ◽  
Marc Bracke ◽  
Ivan Bièche ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Tissue Growth ◽  
Breast Cancer Cell Lines ◽  
Mcf 7

ABSTRACT WISP-2/CCN5 is an estrogen-regulated member of the “connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed” (CCN) family of the cell growth and differentiation regulators. The WISP-2/CCN5 mRNA transcript is undetectable in normal human mammary cells, as well as in highly aggressive breast cancer cell lines, in contrast with its higher level in the breast cancer cell lines characterized by a more differentiated phenotype. We report here that knockdown of WISP-2/CCN5 by RNA interference in estrogen receptor alpha (ERα)-positive MCF-7 breast cancer cells induced an estradiol-independent growth linked to a loss of ERα expression and promoted epithelial-to-mesenchymal transdifferentiation. In contrast, forced expression of WISP-2/CCN5 directed MCF-7 cells toward a more differentiated phenotype. When introduced into the poorly differentiated, estrogen-independent, and invasive MDA-MB-231 breast cancer cells, WISP-2/CCN5 was able to reduce their proliferative and invasive phenotypes. In a series of ERα-positive tumor biopsies, we found a positive correlation between the expression of WISP-2/CCN5 and ID2, a transcriptional regulator of differentiation in normal and transformed breast cells. We propose that WISP-2/CCN5 is an important regulator involved in the maintenance of a differentiated phenotype in breast tumor epithelial cells and may play a role in tumor cell invasion and metastasis.

scholarly journals Potassium channel inhibitors induce oxidative stress in breast cancer cells

2018 ◽  
Vol 11 (4) ◽  
pp. 323-330 ◽  
Author(s):  
Çağri Öner ◽  
Ertuğrul Çolak ◽  
Didem Turgut Coşan
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Potassium Channels ◽  
Potassium Channel ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Mcf 7

AbstractBackgroundAntioxidant levels increase to protect cell homeostasis when oxidant generation is increased by drug or inhibitor treatment. If the oxidant–antioxidant equilibrium is disrupted, oxidative stress will occur.ObjectivesTo determine the effects of various potassium channel inhibitors in the disruption of oxidant–antioxidant equilibrium in breast cancer cell lines with various phenotypes.MethodsMCF-7 or MDA-MB-231 breast cancer cells were treated with tetraethylammonium chloride (5 mM; TEA), 4-aminopyridine (5 mM; 4-AP), margatoxin (25 nM; MgTX), or astemizole (200 nM; AST). After treatment, total antioxidant, oxidant, and oxidative stress levels were determined.ResultsIncubation with TEA, 4-AP, MgTX, and AST increased oxidative stress in both MCF-7 and MDA-MB-231 cells (P < 0.001). Specific inhibitors of calcium-activated potassium channels and ether á go-go 1-related potassium channels produce greater oxidative stress than other inhibitors in MCF-7 breast cancer cells, whereas in MDA-MB-231 cells, the nonselective channel inhibitor 4-AP produces the greatest oxidative stress.ConclusionsPotassium channel inhibitors used in our study disrupted the antioxidant–oxidant equilibrium and increased oxidative stress in the cancer cell lines. Although all of the channel inhibitors increased oxidative stress in cells, TEA and AST were the most effective inhibitors in MCF-7 cells. 4-AP was the most effective inhibitor in MDA-MB-231 cells. Voltage-gated potassium channels are attractive targets for anticancer therapy, and their inhibitors may enhance the effects of anticancer drugs.

Preparation, Characterization and In-vitro Biological Evaluation of Novel Curcumin Derivatives as Cytotoxic and Apoptosis-Inducing Agents

2020 ◽  
Vol 20 ◽  
Author(s):  
Omid K. Arjomandi ◽  
Saiedeh Almasi ◽  
Leila Hosseinzadeh ◽  
Mahboubeh Kavoosi ◽  
Hadi Adibi
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Caspase 3 ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Caspase 9 ◽  
Derivatives Of ◽  
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Background: Curcumin is a natural polyphenol and lead compound of the rhizomes of curcuma longa that it has been widely used for pharmacological activities. Objective: In this study, series of novel derivatives of curcumin, which this group was linked to a 2-amino-4-phenylpyran-3-carbonitrile system, have been synthesized and tested for their antitumor activities in-vitro against a panel of three human cancer cell lines (MCF-7, A2780, and U-87MG). Method: The in-vitro cytotoxic activity of the synthesized compounds was tested on three cancer cell lines (MCF-7, A2780, and U87MG) using MTT colorimetric assay. Meanwhile, the ability of the active compounds to induce apoptosis in cancer cells was investigated by examination of caspase-3 and caspase-9 and mitochondrial membrane potential assay. Results: Under relatively mild conditions in ethanol, the reaction of a series of substrates afforded the corresponding derivatives of curcumin mostly in good yields (13 analogues, 48-94% yields). Bioassay results indicated that compounds L6 (para-Bromo), L9 (paraNitro) and L12 (meta-Methoxy) were the most active members in this study demonstrating potent activities against A2780 cancer cells and experimental results of fluorescent staining and flow cytometry analysis revealed that L6 and L9 could induce apoptosis in A2780 cells with apoptosis ratios of about 40% and 46%, respectively at 24 h of treatment at 15.35 µM and 23µM in A2780 cells. On the other hand, they could increase the caspase-3 activity slightly (10%), while had no significant impact on the activities of caspase-9. Conclusion: Those two derivatives could be considered as useful templates for future development to obtain more potent antitumor agents.

Cytotoxic activity and anti-cancer potential of Ontario grown onion extracts against breast cancer cell lines

2018 ◽  
Vol 8 (3) ◽  
pp. 159 ◽  
Author(s):  
Meghan Fragis ◽  
Abdulmonem I. Murayyan ◽  
Suresh Neethirajan
Keyword(s):  
Breast Cancer ◽  
Cytotoxic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Cytotoxic Activities ◽  
Cancer Line ◽  
Mcf 7

Background: Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths among Canadian women. Cancer management through changes in lifestyle, such as increased intake of foods rich in dietary flavonoids, have been shown to decrease the risk associated with breast, liver, colorectal, and upper-digestive cancers in epidemiologic studies. Onions are high in flavonoid content and one of the most common vegetables. Additionally, onions are used in most Canadian cuisines.Methods: We investigated the effect of five prominent Ontario grown onion (Stanley, Ruby Ring, LaSalle, Fortress, and Safrane) extracts on two subtypes of breast cancer cell lines: a triple negative breast cancer line MDA-MB-231 and an ER+ breast cancer line MCF-7.Results: These onion extracts elicited strong anti-proliferative, anti-migratory, and cytotoxic activities on both the cancer cell lines. Flavonoids present in these onion extracts induced apoptosis, cell cycle arrest in the G2/M phase, and a reduction in mitochondrial membrane potential at dose-dependent concentrations. Onion extracts were more effective against MDA-MB-231 compared to the MCF-7 cell line. Conclusion: In this study, we investigated the extracts synthesized from Ontario-grown onion varieties in inducing anti-migratory, cytostatic, and cytotoxic activities in two sub-types of human breast cancer cell lines. Anti-tumor activity of these extracts depends upon the varietal and can be formulated into nutraceuticals and functional foods for the wellbeing of cancer patients. Overall, the results suggest that onion extracts are a good source of flavonoids with anti-cancerous properties.Keywords: onion extracts; flavonoids; anti-proliferative; breast cancer; cytotoxic activity

Design, Synthesis and Biological Evaluation of 3-(3,4,5-Trimethoxyphenyl)- 5-(2-(5-arylbenzo[b]thiophen-3-yl)oxazol-5-yl)isoxazole Derivatives as Anticancer Agents

2020 ◽  
Vol 17 (5) ◽  
pp. 345-351
Author(s):  
Syndla Premalatha ◽  
G. Rambabu ◽  
Islavathu Hatti ◽  
Dittakavi Ramachandran
Keyword(s):  
Breast Cancer ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Isoxazole Derivatives

A new series of 3-(3,4,5-trimethoxyphenyl)-5-(2-(5-arylbenzo[b]thiophen-3-yl)oxa zol-5- yl)isoxazole derivatives were designed and synthesized. All these derivatives were evaluated for their anticancer activity against various human cancer cell lines such as MCF-7 (breast cancer), A549 (lung cancer), DU-145 (prostate cancer) and MDA MB-231 (breast cancer)-four human cancer cell lines by using MTT assay. Here, etoposide was used as a standard reference drug and most of the compounds were exhibited good anticancer activity with respect to cell lines. Among all compounds, five compounds 11b, 11c, 11f, 11i and 11j showed more potent activity than standard drug, in which, compound 11f was the most promising compound.

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