scholarly journals Evaluation of 2-Thioxoimadazolidin-4-One Derivatives as Potent Anti-Cancer Agents through Apoptosis Induction and Antioxidant Activation: In Vitro and In Vivo Approaches

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 83
Author(s):  
Mohamed S. Nafie ◽  
Ahmed I. Khodair ◽  
Hebat Allah Y. Hassan ◽  
Noha M. Abd El-Fadeal ◽  
Hanin A. Bogari ◽  
...  
Keyword(s):  
Cell Cycle ◽  
In Silico ◽  
Hepg2 Cells ◽  
Flow Cytometric Analysis ◽  
Apoptosis Induction ◽  
Rt Pcr ◽  
Anti Cancer ◽  
Ic50 Values

Background: Hepatocellular carcinoma (HCC) is one of the most widespread malignancies and is reported as the fourth most prevalent cause of cancer deaths worldwide. Therefore, we aimed to investigate the probable mechanistic cytotoxic effect of the promising 2-thioxoimidazolidin-4-one derivative on liver cancer cells using in vitro and in vivo approaches. The compounds were tested for the in vitro cytotoxic activity using MTT assay, and the promising compound was tested in colony forming unit assay, flow cytometric analysis, RT-PCR, Western blotting, in vivo using SEC-carcinoma and in silico to highlight the virtual mechanism of action. Both compounds 4 and 2 performed cytotoxic effects against HepG2 cells with IC50 values of 0.017 and 0.18 μM, respectively, compared to Staurosporine and 5-Fu as reference drugs with IC50 values of 5.07 and 5.18 µM, respectively. Compound 4 treatment revealed apoptosis induction by 19.35-fold (11.42% compared to 0.59% in control), arresting the cell cycle at G2/M phase. Moreover, studying gene expression that plays critical roles in cell cycle and apoptosis by RT-PCR demonstrated that compound 4 enhances the expression of the pro-apoptotic genes p53, PUMA, and Caspase 3, 8, and 9, and impedes the anti-apoptotic Bcl-2 gene in the HepG2 cells. It can also inhibit the PI3K/AKT pathway at both gene and protein levels, which was reinforced by the in silico predictions of the molecular docking simulations towards the PI3K/AKT proteins. Finally, in vivo study verified that compound 4 has a promising anti-cancer activity through activating antioxidant levels (CAT, SOD and GSH) and ameliorating hematological, biochemical, and histopathological findings.

scholarly journals Trilobatin, a Novel SGLT1/2 Inhibitor, Selectively Induces the Proliferation of Human Hepatoblastoma Cells

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3390 ◽  
Author(s):  
Lujing Wang ◽  
Min Liu ◽  
Fei Yin ◽  
Yuanqiang Wang ◽  
Xingan Li ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
S Phase ◽  
Hepatocyte Proliferation ◽  
Hepatocyte Nuclear Factor ◽  
Interacting Protein ◽  
Glucose Lowering ◽  
Anti Cancer ◽  
High Concentrations

Studies have indicated that Na+-d-glucose co-transporter (SGLT) inhibitors had anti-proliferative activity by attenuating the uptake of glucose in several tumor cell lines. In this study, the molecular docking showed that, trilobatin, one of the dihydrochalcones from leaves of Lithocarpus polystachyus Rehd., might be a novel inhibitor of SGLT1 and SGLT2, which evidently attenuated the uptake of glucose in vitro and in vivo. To our surprise, we observed that trilobatin did not inhibit, but promoted the proliferation of human hepatoblastoma HepG2 and Huh 7 cells when it was present at high concentrations. At the same time, incubation with high concentrations of trilobatin arrested the cell cycle at S phase in HepG2 cells. We also found that treatment with trilobatin had no significant effect on the expression of hepatitis B x-interacting protein (HBXIP) and hepatocyte nuclear factor (HNF)-4α, the two key regulators of hepatocyte proliferation. Taken together, although trilobatin worked as a novel inhibitor of SGLTs to attenuate the uptake of glucose, it also selectively induced the cell proliferation of HepG2 cells, suggesting that not all the SGLT inhibitors inhibited the proliferation of tumor cells, and further studies are needed to assess the anti-cancer potentials of new glucose-lowering agents.

Per2 Inhibits K562 Leukemia Cell Growth In Vitro and In Vivo Through Cell Cycle Arrest and Apoptosis Induction

2009 ◽  
Vol 16 (3) ◽  
pp. 403-411 ◽  
Author(s):  
Cheng-ming Sun ◽  
Shi-feng Huang ◽  
Jian-ming Zeng ◽  
Din-bing Liu ◽  
Qing Xiao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Leukemia Cell ◽  
Apoptosis Induction ◽  
Cycle Arrest

scholarly journals In silico screening leads to novel scaffolds with both antifungal and anti-NLRP3 inflammasome activity

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
David Lowes ◽  
Rand Al-waqfi ◽  
Kirk Hevener ◽  
Brian Peters
Keyword(s):  
Nlrp3 Inflammasome ◽  
In Silico ◽  
Fungal Growth ◽  
Hyphal Growth ◽  
Acetohydroxyacid Synthase ◽  
In Silico Screening ◽  
Chemical Structures ◽  
Ic50 Values

Due to structural similarities that exist between established inhibitors of the NLRP3-inflammasome, sulfonylureas Glyburide and MCC-950, and herbicidal-sulfonylureas, that specifically target fungal acetohydroxyacid synthase (AHAS), we sought to determine the potential for compounds to block both inflammation and inhibit fungal growth. In silico screening of ∼250,000 compounds was used to identify a prioritized list of chemical structures capable of inhibiting both targets. Prioritization of the top 1% of scores identified ∼70 compounds with a diverse set of scaffolds for testing in vitro. Selected hits were used to assess anti-inflammatory function in a THP-1 challenge model with LPS+ATP and resulting IC50 values were obtained. MIC and hyphal-growth assays were conducted to determine potential antifungal activity using media depleted of branched chain amino acids isoleucine and valine, to confirm on target AHAS inhibition. Identification of hits that exhibited low micromolar activity for NLRP3 and AHAS inhibition were selected for SAR study. In vitro testing of the analogs along with molecular docking led to increased knowledge for lead optimization of the potential hits. In silico screening has resulted in IC50 (IL-1β release) and MIC50 (fungal growth) values with low μM potency against several Candida species. In vivo validation will further confirm the potential of the scaffolds for further synthetic-modification for the rationale design of novel dual-purpose drugs

Prediction of Acute Toxicity in HPCT-1E3 Hepatocytoma Cells with Liver-like Transport Activities

2007 ◽  
Vol 35 (4) ◽  
pp. 411-420 ◽  
Author(s):  
Carsten Kneuer ◽  
Cathleen Lakoma ◽  
Walther Honscha
Keyword(s):  
Hepg2 Cells ◽  
Transport Processes ◽  
Coefficient Of Determination ◽  
Serum Concentrations ◽  
Oral Toxicity ◽  
Ic50 Values ◽  
Order Of Magnitude ◽  
Lethal Doses

A battery of in vitro methods has been developed for the prediction of acute oral toxicity, to reduce the number of animals used for this purpose. However, the results of these tests correlate more closely with lethal serum concentrations than with lethal doses. To address this issue, we have further evaluated the HPCT-1E3 model, which may be better able to emulate toxicokinetic factors that occur in vivo, due to the presence in these hepatocytoma cells of endogenous transmembrane carriers and a basal activity of xenobiotic metabolism. IC50 values produced by using the MTT test after a 48-hour incubation with 20 randomly-selected MEIC substances, correlated better with human oral LD50 values than with LC50 data, supporting this hypothesis. As with other models, the toxicity of receptor-specific rather than cytotoxic substances, for example digoxin, was underpredicted. When digoxin was removed from the correlation analysis, the coefficient of determination (r2) improved to 0.81, and none of remaining chemicals were wrongly predicted by more than one order of magnitude. IC50 values obtained with HepG2 cells under similar conditions (MEIC Test No. 3, 24 hours, MTT) correlated with human LD50 data with a r2 value of 0.55. A direct comparison of HPCT-1E3 and HepG2 cells further suggested that the differences between them may be due to transport processes. In conclusion, the HPCT-1E3 model may be valuable in improving the prediction of lethal doses, rather than lethal serum concentrations.

Mesenchymal Stromal Cells Expressing Interferon α Limit the Development of Acute Myeloid Leukemia, Inducing Apoptosis In Vitro and In Vivo

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5216-5216
Author(s):  
Laura M Desbourdes ◽  
Adam J Guess ◽  
Suheyla Hasgur ◽  
Kathleen M Overholt ◽  
Minjun Yu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Myeloid Leukemia ◽  
Stromal Cells ◽  
Myeloid Leukemia ◽  
Flow Cytometric Analysis ◽  
Interferon Α ◽  
Flow Cytometric ◽  
Acute Myeloid

Abstract Introduction The 5-year survival for patients with acute myeloid leukemia (AML) has stagnated for over two decades at about 60% for children, 40% for young adults, and <15% for elderly patients. While most patients achieve remission, approximately 50% will relapse which is generally attributed to the persistence of leukemic stem cells. Interferon α (IFNα) is an effective therapy for patients with AML due to multiple mechanisms of action. However, high serum levels are associated with many adverse effects. In this proof-of-concept study, we used engineered mesenchymal stem/stromal cells (MSC) to deliver high concentrations of IFNα locally to an AML chloroma, potentially diminishing the poorly tolerated systemic side-effects. Methods Bone marrow MSCs from C57BL/6 mouse were isolated and transduced with a lentiviral vector expressing murine IFNα (IFNα-MSCs) and/or GFP (GFP MSCs). After measuring IFNα secretion by ELISA and confirming activity by the induction of the MHC I expression on the transduced cells, the anti-AML activity of these transduced MSCs was assessed by co-culture with the C57BL/6 AML cell line c1498 which expresses DsRed and firefly luciferase (FFluc). Apoptotic cell frequencies and cell cycle phase distributions of leukemia cells with or without MSCs were assessed by flow cytometry. The in vivo validation has been performed by subcutaneous injection of c1498 cells (chloroma) with or without GFP MSCs or IFNα MSCs in C57BL/6 mice. Tumor growth was monitored by bioluminescence imaging every 3 or 4 days. Results Flow cytometric analysis and ELISA confirmed the secretion of bio-active of IFNα by transduced MSCs (41.5 ng/1E06 MSCs/24h). In co-cultures, the presence of IFNα MSCs at the ratio 100:1 (c1498: MSC) significantly decreased the population of c1498 cells mainly by inducing apoptosis compared to MSC-free or GFP MSC co-cultures while no effect was observed on cell cycle distribution. The pro-apoptotic effect of IFNα MSCs was then investigated in vivo by subcutaneous injection of c1498 cells with or without MSCs (ratio 10:1) in C57BL/6 mice.The presence of IFNα MSCs significantly decreased leukemic cell mass as shown by the bioluminescence of the DsRed+ FFLuc+ c1498 cells. This result was confirmed by flow cytometric analysis of the percentage of DsRed + cells in the chloroma. Conclusions This study shows that IFNα MSCs present a strong anti-leukemic effect in vitro and in vivo promoting apoptosis and thus decreasing the leukemic burden. Further experiments will focus on a potential synergetic effect with Cytarabine treatment and a preclinical study using human IFNα MSCs in a xenograft murine model. Disclosures No relevant conflicts of interest to declare.

scholarly journals α-Tomatine-Mediated Anti-Cancer Activity In Vitro and In Vivo through Cell Cycle- and Caspase-Independent Pathways

PLoS ONE ◽  
2012 ◽  
Vol 7 (9) ◽  
pp. e44093 ◽  
Author(s):  
Min-Wu Chao ◽  
Chun-Han Chen ◽  
Ya-Ling Chang ◽  
Che-Ming Teng ◽  
Shiow-Lin Pan
Keyword(s):  
Cell Cycle ◽  
Anti Cancer ◽  
Cancer Activity

scholarly journals In vivo modulation of 4E binding protein 1 (4E-BP1) phosphorylation by watercress: a pilot study

2010 ◽  
Vol 104 (9) ◽  
pp. 1288-1296 ◽  
Author(s):  
Sharifah S. Syed Alwi ◽  
Breeze E. Cavell ◽  
Urvi Telang ◽  
Marilyn E. Morris ◽  
Barbara M. Parry ◽  
...  
Keyword(s):  
Pilot Study ◽  
Dietary Intake ◽  
Cancer Cell ◽  
Peripheral Blood ◽  
Binding Protein ◽  
Flow Cytometric Analysis ◽  
Maximum Plasma ◽  
Anti Cancer

Dietary intake of isothiocyanates (ITC) has been associated with reduced cancer risk. The dietary phenethyl ITC (PEITC) has previously been shown to decrease the phosphorylation of the translation regulator 4E binding protein 1 (4E-BP1). Decreased 4E-BP1 phosphorylation has been linked to the inhibition of cancer cell survival and decreased activity of the transcription factor hypoxia-inducible factor (HIF), a key positive regulator of angiogenesis, and may therefore contribute to potential anti-cancer effects of PEITC. In the present study, we have investigated the in vitro and in vivo effects of watercress, which is a rich source of PEITC. We first demonstrated that, similar to PEITC, crude watercress extracts inhibited cancer cell growth and HIF activity in vitro. To examine the effects of dietary intake of watercress, we obtained plasma and peripheral blood mononuclear cells following the ingestion of an 80 g portion of watercress from healthy participants who had previously been treated for breast cancer. Analysis of PEITC in plasma samples from nine participants demonstrated a mean maximum plasma concentration of 297 nm following the ingestion of watercress. Flow cytometric analysis of 4E-BP1 phosphorylation in peripheral blood cells from four participants demonstrated significantly reduced 4E-BP1 phosphorylation at 6 and 8 h following the ingestion of watercress. Although further investigations with larger numbers of participants are required to confirm these findings, this pilot study suggests that flow cytometry may be a suitable approach to measure changes in 4E-BP1 phosphorylation following the ingestion of watercress, and that dietary intake of watercress may be sufficient to modulate this potential anti-cancer pathway.

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