scholarly journals Marine Actinomycetes-Derived Secondary Metabolites Overcome TRAIL-Resistance via the Intrinsic Pathway through Downregulation of Survivin and XIAP

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1760 ◽  
Author(s):  
Mohammed I. Y. Elmallah ◽  
Sheron Cogo ◽  
Andrei A. Constantinescu ◽  
Selene Elifio-Esposito ◽  
Mohammed S. Abdelfattah ◽  
...  
Keyword(s):  
Cell Death ◽  
Secondary Metabolites ◽  
Cell Lines ◽  
Hct116 Cell ◽  
Cancer Cell Line ◽  
Cancer Drug ◽  
Dependent Manner ◽  
Marine Actinomycetes ◽  
Intrinsic Pathway ◽  
Concentration Dependent Manner

Resistance of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis represents the major hurdle to the clinical use of TRAIL or its derivatives. The discovery and development of lead compounds able to sensitize tumor cells to TRAIL-induced cell death is thus likely to overcome this limitation. We recently reported that marine actinomycetes’ crude extracts could restore TRAIL sensitivity of the MDA-MB-231 resistant triple negative breast cancer cell line. We demonstrate in this study, that purified secondary metabolites originating from distinct marine actinomycetes (sharkquinone (1), resistomycin (2), undecylprodigiosin (3), butylcyclopentylprodigiosin (4), elloxizanone A (5) and B (6), carboxyexfoliazone (7), and exfoliazone (8)), alone, and in a concentration-dependent manner, induce killing in both MDA-MB-231 and HCT116 cell lines. Combined with TRAIL, these compounds displayed additive to synergistic apoptotic activity in the Jurkat, HCT116 and MDA-MB-231 cell lines. Mechanistically, these secondary metabolites induced and enhanced procaspase-10, -8, -9 and -3 activation leading to an increase in PARP and lamin A/C cleavage. Apoptosis induced by these compounds was blocked by the pan-caspase inhibitor QvD, but not by a deficiency in caspase-8, FADD or TRAIL agonist receptors. Activation of the intrinsic pathway, on the other hand, is likely to explain both their ability to trigger cell death and to restore sensitivity to TRAIL, as it was evidenced that these compounds could induce the downregulation of XIAP and survivin. Our data further highlight that compounds derived from marine sources may lead to novel anti-cancer drug discovery.

scholarly journals Anticancer effects of mifepristone on human uveal melanoma cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Prisca Bustamante Alvarez ◽  
Alexander Laskaris ◽  
Alicia A. Goyeneche ◽  
Yunxi Chen ◽  
Carlos M. Telleria ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Progesterone Receptor ◽  
Dna Fragmentation ◽  
Cell Lines ◽  
Caspase 3 ◽  
Annexin V ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Free Dna

Abstract Background Uveal melanoma (UM), the most prevalent intraocular tumor in adults, is a highly metastatic and drug resistant lesion. Recent studies have demonstrated cytotoxic and anti-metastatic effects of the antiprogestin and antiglucocorticoid mifepristone (MF) in vitro and in clinical trials involving meningioma, colon, breast, and ovarian cancers. Drug repurposing is a cost-effective approach to bring approved drugs with good safety profiles to the clinic. This current study assessed the cytotoxic effects of MF in human UM cell lines of different genetic backgrounds. Methods The effects of incremental concentrations of MF (0, 5, 10, 20, or 40 μM) on a panel of human UM primary (MEL270, 92.1, MP41, and MP46) and metastatic (OMM2.5) cells were evaluated. Cells were incubated with MF for up to 72 h before subsequent assays were conducted. Cellular functionality and viability were assessed by Cell Counting Kit-8, trypan blue exclusion assay, and quantitative label-free IncuCyte live-cell analysis. Cell death was analyzed by binding of Annexin V-FITC and/or PI, caspase-3/7 activity, and DNA fragmentation. Additionally, the release of cell-free DNA was assessed by droplet digital PCR, while the expression of progesterone and glucocorticoid receptors was determined by quantitative real-time reverse transcriptase PCR. Results MF treatment reduced cellular proliferation and viability of all UM cell lines studied in a concentration-dependent manner. A reduction in cell growth was observed at lower concentrations of MF, with evidence of cell death at higher concentrations. A significant increase in Annexin V-FITC and PI double positive cells, caspase-3/7 activity, DNA fragmentation, and cell-free DNA release suggests potent cytotoxicity of MF. None of the tested human UM cells expressed the classical progesterone receptor in the absence or presence of MF treatment, suggesting a mechanism independent of the modulation of the cognate nuclear progesterone receptor. In turn, all cells expressed non-classical progesterone receptors and the glucocorticoid receptor. Conclusion This study demonstrates that MF impedes the proliferation of UM cells in a concentration-dependent manner. We report that MF treatment at lower concentrations results in cell growth arrest, while increasing the concentration leads to lethality. MF, which has a good safety profile, could be a reliable adjuvant of a repurposing therapy against UM.

scholarly journals Anticancer Effects of Mifepristone on Human Uveal Melanoma Cells

2021 ◽  
Author(s):  
Alexander Laskaris ◽  
Prisca Bustamante ◽  
Alicia A. Goyeneche ◽  
Carlos M. Telleria ◽  
Julia V Burnier
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Progesterone Receptor ◽  
Dna Fragmentation ◽  
Cell Lines ◽  
Uveal Melanoma ◽  
Annexin V ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Free Dna

Abstract Background: Uveal melanoma (UM), the most prevalent intraocular tumor in adults, is a highly metastatic and drug resistant cancer. Recent studies have demonstrated cytotoxic and anti-metastatic effects of the antiprogestin and antiglucocorticoid mifepristone (MF) in vitro and in clinical trials involving meningioma, colon, breast, and ovarian cancers. Drug repurposing is a cost-effective approach to bring approved drugs with good safety profiles to the clinic. This current study assessed the cytostatic and cytotoxic effects of MF in human UM cell lines of different genetic backgrounds.Methods: The effects of incremental concentrations of MF (0, 5, 10, 20, 30 or 40 mM) on a panel of human UM primary (MP46, 92.1, MP41, MEL270) and metastatic (OMM2.5) cells were evaluated. Cells were incubated with MF for up to 72 hours before subsequent assays were conducted. Cellular functionality and viability were assessed by Cell Counting Kit-8, trypan blue exclusion assay, and quantitative label-free IncuCyte live-cell analysis. Cell death was analyzed by binding of Annexin V-FITC and/or propidium iodide (PI), caspases 3/7 activities, and DNA fragmentation. Additionally, the release of cell-free DNA was assessed by ddPCR, while the expression of progesterone and glucocorticoid receptors was determined by qPCR. Results: MF treatment reduced cellular proliferation and viability of all UM cell lines studied in a concentration-dependent manner. A reduction in cell growth was observed at lower concentrations of MF, with evidence of cell death at higher concentrations. A significant increase in Annexin V-FITC and PI-double positive cells, caspase 3/7 activities, DNA fragmentation, and cell-free DNA release suggests potent cytotoxicity of MF. None of the tested human UM cells expressed the classical progesterone receptor in the absence or presence of MF treatment, suggesting a mechanism independent of the modulation of the cognate nuclear progesterone receptor. In turn, all cells expressed non-classical progesterone receptors and the glucocorticoid receptor. Conclusion: This study demonstrates that MF impedes the proliferation of UM cells in a concentration-dependent manner. We report that MF treatment at lower concentrations results in cell growth arrest, while increasing the concentration leads to lethality. MF, which has a good safety profile, could be a reliable adjuvant of a repurposing therapy against UM.

Design, Synthesis and Cytotoxicity Evaluation of New 3, 5-Disubstituted-2-Thioxoimidazolidinones

2018 ◽  
Vol 18 (4) ◽  
pp. 573-582 ◽  
Author(s):  
Khaled R.A. Abdellatif ◽  
Mostafa M. Elbadawi ◽  
Mohammed T. Elsaady ◽  
Amer A. Abd El-Hafeez ◽  
Takashi Fujimura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Topoisomerase I ◽  
Cancer Cell Line ◽  
Cytotoxic Agents ◽  
Dependent Manner ◽  
Human Lung Fibroblast ◽  
Mcf 7

Background: Some 2-thioxoimidazolidinones have been reported as anti-prostate and anti-breast cancer agents through their inhibitory activity on topoisomerase I that is considered as a potential chemotherapeutic target. Objective: A new series of 3,5-disubstituted-2-thioxoimidazolidinone derivatives 10a-f and their S-methyl analogs 11a-f were designed, synthesized and evaluated for cytotoxicity against human prostate cancer cell line (PC-3), human breast cancer cell line (MCF-7) and non-cancerous human lung fibroblast cell line (WI-38). </P><P> Results and Method: While compounds 10a-f showed a broad range of activities against PC-3 and MCF-7 cell lines (IC50 = 34.0 – 186.9 and 24.6 – 147.5 µM respectively), the S-methyl analogs 11a-f showed (IC50 = 22.7 – 198.5 and 16.9 – 188.2 µM respectively) in comparison with 5-fluorouracil (IC50 = 60.7 and 40.7 µM respectively). 11c (IC50 = 22.7 and 29.2 µM) and 11f (IC50 = 28.7 and 16.9 µM) were the most potent among all compounds against both PC-3 and MCF-7 respectively with no cytotoxicity against WI-38. Conclusion: The newly synthesized compounds showed good activity against PC-3 and MCF-7 cell lines in comparison with 5-fluorouracil. Compounds 11c and 11f bound with human topoisomerase I similar to its known inhibitors and significantly inhibited its DNA relaxation activity in a dose dependent manner which may rationalize their molecular mechanism as cytotoxic agents.

scholarly journals Human Neuronal Cell Lines as An In Vitro Toxicological Tool for the Evaluation of Novel Psychoactive Substances

2021 ◽  
Vol 22 (13) ◽  
pp. 6785
Author(s):  
Valeria Sogos ◽  
Paola Caria ◽  
Clara Porcedda ◽  
Rafaela Mostallino ◽  
Franca Piras ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell ◽  
In Vitro Study ◽  
Dependent Manner ◽  
Novel Psychoactive Substances ◽  
Psychoactive Substances ◽  
Concentration Dependent Manner ◽  
Mechanisms Of Toxicity ◽  
Neuronal Cell Lines

Novel psychoactive substances (NPS) are synthetic substances belonging to diverse groups, designed to mimic the effects of scheduled drugs, resulting in altered toxicity and potency. Up to now, information available on the pharmacology and toxicology of these new substances is very limited, posing a considerable challenge for prevention and treatment. The present in vitro study investigated the possible mechanisms of toxicity of two emerging NPS (i) 4′-methyl-alpha-pyrrolidinoexanophenone (3,4-MDPHP), a synthetic cathinone, and (ii) 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA), a phenethylamine. In addition, to apply our model to the class of synthetic opioids, we evaluated the toxicity of fentanyl, as a reference compound for this group of frequently abused substances. To this aim, the in vitro toxic effects of these three compounds were evaluated in dopaminergic-differentiated SH-SY5Y cells. Following 24 h of exposure, all compounds induced a loss of viability, and oxidative stress in a concentration-dependent manner. 2-Cl-4,5-MDMA activates apoptotic processes, while 3,4-MDPHP elicits cell death by necrosis. Fentanyl triggers cell death through both mechanisms. Increased expression levels of pro-apoptotic Bax and caspase 3 activity were observed following 2-Cl-4,5-MDMA and fentanyl, but not 3,4-MDPHP exposure, confirming the different modes of cell death.

scholarly journals The Modulation of PCSK9 and LDLR by Supercritical CO2 Extracts of Mentha longifolia and Isolated Piperitone Oxide, an In Vitro Study

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3886
Author(s):  
Stefania Sut ◽  
Irene Ferrarese ◽  
Maria Giovanna Lupo ◽  
Nicola De Zordi ◽  
Elisa Tripicchio ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Lines ◽  
Hepatoma Cell ◽  
Density Lipoprotein ◽  
In Vitro Study ◽  
Volatile Constituent ◽  
Dependent Manner ◽  
Human Hepatoma Cell ◽  
Concentration Dependent Manner

In the present study the ability of supercritical carbon dioxide (SCO2) extracts of M. longifolia L. leaves to modulate low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression was evaluated in cultured human hepatoma cell lines Huh7 and HepG2. Two SCO2 extracts, one oil (ML-SCO2) and a semisolid (MW-SCO2), were subjected to detailed chemical characterization by mono- and bidimensional nuclear magnetic resonance (1D, 2D-NMR), gas chromatography coupled with mass spectrometry (GC-MS) and liquid chromatography coupled with mass spectrometry (LC-MS). Chemical analysis revealed significant amounts of fatty acids, phytosterols and terpenoids. ML-SCO2 was able to induce LDLR expression at a dose of 60 µg/mL in HuH7 and HepG2 cell lines. Furthermore, ML-SCO2 reduced PCSK9 secretion in a concentration-dependent manner in both cell lines. Piperitone oxide, the most abundant compound of the volatile constituent of ML-SCO2 (27% w/w), was isolated and tested for the same targets, showing a very effective reduction of PCSK9 expression. The overall results revealed the opportunity to obtain a new nutraceutical ingredient with a high amount of phytosterols and terpenoids using the SCO2 extraction of M. longifolia L., a very well-known botanical species used as food. Furthermore, for the first time we report the high activity of piperitone oxide in the reduction of PCSK9 expression.

scholarly journals Inhibition of HepG-2 Cells (Liver Cancer Cell Line) Viability by 3-Hydroxypyridine-2-Carboxaldehyde N(4)-Methylthiosemicarbazone

2021 ◽  
Vol 8 (2) ◽  
pp. 88-97
Author(s):  
Edrees Khan Rahmatzada ◽  
Prof. Paras Nath Yadav ◽  
Dr. Yuba Raj Pokharel
Keyword(s):  
Cancer Cell Line ◽  
Mapk Signaling ◽  
In Vivo Model ◽  
Dependent Manner ◽  
Dapi Staining ◽  
Concentration Dependent Manner ◽  
Anticancer Effects ◽  
Ic50 Value ◽  
Colony Number

Thiosemicarbazone have the antiviral, antibacterial, antifungal, and anticancer effects. 3-OH-Me-TSC inhibited the cell viability of HepG-2 cells by CV assay in a concentration dependent manner (control, 1μM, 3μM, 10μM, 30μM, and 100μM) with IC50 value of 9.587622μM. Further colony formation assay demonstrated that 3-OH-Me-TSC inhibits colony number and size of HepG-2. Wound healing assay exhibited that 3-OH-Me-TSC inhibit the migration of HepG-2 cells. DAPI staining showed that 3-OH-Me-TSC inhibited proliferation of HepG-2 cells in 30μM and 100μM concentrations respectively. 3-OH-Me-TSC inhibited VEGF, p38 alpha, C-JUN, BECN-1, ERK, NF-KB, in HepG-2 cells. We found that 3-OH-Me-TSC inhibit proliferation of HepG-2 cells by inhibiting MAPK signaling pathway, 3-OH-Me-TSC can be developed as future chemotherapeutic agent for treatment of hepatocellular carcinoma after the evaluation of this compounds in more cancer cells an in vivo model.

scholarly journals In vitroAnticancer Evaluation of Saponins Obtained From Spirulina platensis on MDA, HepG2, and MCF7 Cell Lines

2019 ◽  
Vol 3 (4) ◽  
pp. 25-32
Author(s):  
Mahboobeh Akbarizare ◽  
Hamideh Ofoghi ◽  
Mahnaz Hadizadeh
Keyword(s):  
Cell Lines ◽  
Anticancer Agents ◽  
Spirulina Platensis ◽  
Dependent Manner ◽  
Cellular Viability ◽  
Breast Cancers ◽  
Anticancer Activities ◽  
Concentration Dependent Manner ◽  
Photosynthetic Microorganism ◽  
Mcf 7

Introduction: Microalgae are known for their bioactive compounds with potential applications as antimicrobial, antiaging, and anticancer activities. Spirulina platensis (S. platensis) is a filamentous and photosynthetic microorganism that has 25 kinds of vitamins and minerals that contain many compounds with biotic activity such as alkaloids, phenolic compounds, terpenoids, and saponins. Saponins are mainly present in plants; while there are few studies about their role in microalgae. This study aims to investigate the anticancer potential of extracted saponins from S. platensis. Methods: Saponins were extracted; using distilled water and n-butanol. The total extracted saponin was dried and weighed. The cellular viability of HepG2, MCF-7, and MDA- MB-123 cell lines was evaluated; using MTT assay after 24 h treatment with 0.02-2 mg/ ml of saponins extracted from S. platensis. Morphology of cell lines was evaluated by invert microscopy. Results: Total saponin extracted from S. platensis was estimated at 28±0.0005 mg/g dry wt. Thin-layer chromatography profiles showed four bands for saponins with Rf values of 0.44, 0.48, 0.50, and 0.55. The cytotoxic activity after 24 h treatment with 0.02-2 mg/ml of saponins was a concentration-dependent manner. The highest toxicity of saponins with IC50=0.22 mg/ml was observed in MDA-MB-123 cells. In HepG2 and MCF-7 cells IC50 value was obtained in 0.35 mg/ml and 0.4 mg/ml, respectively. Conclusions: This is the first report to evaluate the anticancer effects of saponins from S. platensis in liver and breast cancers. The result showed that saponins from Spirulina decrease cancer cellular viability. Therefore, these compounds can be a candidate for anticancer agents.

Synthesis and Biological Evaluation of Novel 4-Phenylaminobenzofuro[2,3-d]pyrimidine Derivatives

2020 ◽  
Vol 42 (4) ◽  
pp. 564-564
Author(s):  
Ju liu Ju liu ◽  
Jun Li Jun Li ◽  
Jian tao Shi Jian tao Shi ◽  
Jie Li Jie Li ◽  
Xue chen Hao Xue chen Hao ◽  
...  
Keyword(s):  
Cell Lines ◽  
A549 Cells ◽  
Positive Control ◽  
Biological Evaluation ◽  
Dependent Manner ◽  
Pyrimidine Derivatives ◽  
Concentration Dependent Manner ◽  
Ic50 Value ◽  
Synthesis And Biological Evaluation

A series of novel 4-phenylaminobenzofuro[2,3-d]pyrimidine derivatives had been prepared and assessed for their in vitro antiproliferative activities against three lung cancer cell lines (A549, H460 and H1975). The bioassay results showed most of the designed compounds exhibited potential antiproliferation activities. Among them, compound 8f exhibited remarkable inhibitory activity against A549 and H460 cell lines with IC50 value of 2.54 μM and 2.68 μM, respectively, which was comparable to that of the positive control sorafenib (IC50 = 2.69 μM for A549 and 3.71 μM for H460). AO/EB staining suggests that compound 8f could induce apoptosis in A549 cells. Furthermore, cell cycle analyses show that compound 8f increased G0/G1 A549 cells arrest in a concentration-dependent manner. The preliminary structure-activity relationships (SARs) studies indicated that mono-electron-withdrawing groups (mono-EWGs) on the phenyl ring are positive on the antitumor activity.

scholarly journals Design, Synthesis and Biological Evaluation of a New Series of 1-Aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea Derivatives as Antiproliferative Agents

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2108 ◽  
Author(s):  
Chuanming Zhang ◽  
Xiaoyu Tan ◽  
Jian Feng ◽  
Ning Ding ◽  
Yongpeng Li ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
A549 Cells ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Urea Derivatives ◽  
Antiproliferative Agents

To discover new antiproliferative agents with high efficacy and selectivity, a new series of 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea derivatives (7a–7t) were designed, synthesized and evaluated for their antiproliferative activity against A549, HCT-116 and PC-3 cancer cell lines in vitro. Most of the target compounds demonstrated significant antiproliferative effects on all the selective cancer cell lines. Among them, the target compound, 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-{4-{{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}thio}phenyl}urea (7i) was identified to be the most active one against three cell lines, which was more potent than the positive control with an IC50 value of 1.53 ± 0.46, 1.11 ± 0.34 and 1.98 ± 1.27 μM, respectively. Further cellular mechanism studies confirmed that compound 7i could induce the apoptosis of A549 cells in a concentration-dependent manner and elucidated compound 7i arrests cell cycle at G1 phase by flow cytometry analysis. Herein, the studies suggested that the 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea skeleton might be regarded as new chemotypes for designing effective antiproliferative agents.

scholarly journals TGF-β Promotes the Proliferation of Microglia In Vitro

2019 ◽  
Vol 10 (1) ◽  
pp. 20 ◽  
Author(s):  
Costansia Bureta ◽  
Takao Setoguchi ◽  
Yoshinobu Saitoh ◽  
Hiroyuki Tominaga ◽  
Shingo Maeda ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Transforming Growth Factor Beta ◽  
Microglial Cell ◽  
Transforming Growth Factor ◽  
Dependent Manner ◽  
In Vitro Proliferation ◽  
Inhibition Of Proliferation ◽  
Significant Difference

The activation and proliferation of microglia is characteristic of the early stages of brain pathologies. In this study, we aimed to identify a factor that promotes microglial activation and proliferation and examined the in vitro effects on these processes. We cultured microglial cell lines, EOC 2 and SIM-A9, with various growth factors and evaluated cell proliferation, death, and viability. The results showed that only transforming growth factor beta (TGF-β) caused an increase in the in vitro proliferation of both microglial cell lines. It has been reported that colony-stimulating factor 1 promotes the proliferation of microglia, while TGF-β promotes both proliferation and inhibition of cell death of microglia. However, upon comparing the most effective doses of both (assessed from the proliferation assay), we identified no statistically significant difference between the two factors in terms of cell death; thus, both have a proliferative effect on microglial cells. In addition, a TGF-β receptor 1 inhibitor, galunisertib, caused marked inhibition of proliferation in a dose-dependent manner, indicating that inhibition of TGF-β signalling reduces the proliferation of microglia. Therefore, galunisertib may represent a promising therapeutic agent for the treatment of neurodegenerative diseases via inhibition of nerve injury-induced microglial proliferation, which may result in reduced inflammatory and neuropathic and cancer pain.

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