An Insight into the Mechanism of Holamine- and Funtumine-Induced Cell Death in Cancer Cells

Holamine and funtumine, steroidal alkaloids with strong and diverse pharmacological activities are commonly found in the Apocynaceae family of Holarrhena. The selective anti-proliferative and cell cycle arrest effects of holamine and funtumine on cancer cells have been previously reported. The present study evaluated the anti-proliferative mechanism of action of these two steroidal alkaloids on cancer cell lines (HT-29, MCF-7 and HeLa) by exploring the mitochondrial depolarization effects, reactive oxygen species (ROS) induction, apoptosis, F-actin perturbation, and inhibition of topoisomerase-I. The apoptosis-inducing effects of the compounds were studied by flow cytometry using the APOPercentageTM dye and Caspase-3/7 Glo assay kit. The two compounds showed a significantly greater cytotoxicity in cancer cells compared to non-cancer (normal) fibroblasts. The observed antiproliferative effects of the two alkaloids presumably are facilitated through the stimulation of apoptosis. The apoptotic effect was elicited through the modulation of mitochondrial function, elevated ROS production, and caspase-3/7 activation. Both compounds also induced F-actin disorganization and inhibited topoisomerase-I activity. Although holamine and funtumine appear to have translational potential for the development of novel anticancer agents, further mechanistic and molecular studies are recommended to fully understand their anticancer effects.

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Induction of cell cycle arrest and apoptosis by copper complex Cu(SBCM)2 towards oestrogen-receptor positive MCF-7 breast cancer cells

RSC Advances ◽

10.1039/c9ra03130h ◽

2019 ◽

Vol 9 (32) ◽

pp. 18359-18370 ◽

Cited By ~ 3

Author(s):

Jhi Biau Foo ◽

Li Shan Ng ◽

Ji Hui Lim ◽

Pau Xien Tan ◽

Yan Zhi Lor ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Topoisomerase I ◽

Oestrogen Receptor ◽

Breast Cancer Cells ◽

Dna Topoisomerase ◽

Cycle Arrest ◽

Mcf 7

Cu(SBCM)2 binds to DNA topoisomerase I, which, in turn, induces cell cycle arrest and apoptosis in MCF-7 breast cancer cells, possibly via p53 signalling pathway.

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Cytotoxicity and Toxicological Studies of Artocarpus altilis Extracts, Inducing Apoptosis and Cell Cycle Arrest via CASPASE-3 and CASPASE-8 Pathways Against Human Breast MCF-7 Cells

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207324666210302095557 ◽

2021 ◽

Vol 24 ◽

Author(s):

Tara Jalal ◽

Hatim Abdullah Natto ◽

Ridhwan Abdul Wahab

Keyword(s):

Cell Cycle ◽

Phenolic Compounds ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Caspase 3 ◽

Mrna Levels ◽

Dependent Manner ◽

Methanol Extracts ◽

Cycle Arrest ◽

Mcf 7

: In recent biomedical research, the area of cancer and infectious diseases has a leading position in the utilization of medicinal plants as a source of drug discovery. Malaysia has a diversity and a large number of underutilized fruits that are rich in phenolic compounds. Artoarpus altilis consider an underutilized fruit that is rich in phenolic compounds. Methanol extracts of A. altilis have been previously found to contain a high content of antioxidant phytochemicals. The purpose of the study was to evaluate the cytotoxicity and toxicological effect of methanol fruit extracts against MCF-7 cells. To determine the least concentration that might kill or suppress the growth of the cancer cells was in a concentration-dependent manner approach. The variation in the cytotoxic activity among the extracts was indicated by determining the IC50 of each extract against cells at 72 h. The IC50 of the samples was measured using a trypan blue exclusion assay. The methanol extract of the pulp part showed the least inhibition concentration of 15.40±0.91 μg/mL on MCF-7 cells. In the study, the molecular mechanism of methanol extracts-induced apoptosis and cell cycle arrested in human cancer cells were investigated in a time-dependent-manners approach by using flow cytometry. The treated cells were stained with nexin to detect early and late apoptosis and with propidium iodide (PI) for cell cycle arrest associated with the DNA fragmentation, various cell arrests occurred at G1/S, S, and G2/M phases. Lastly, the gene expression analysis by (RT-qPCR) method was carried out by analyzing the expression of the gene of interest for the quantification of mRNA levels. Results after cells treated with IC50 were revealed by upregulating anti-apoptotic genes/downregulated of pro-apoptotic BCL-2 gene expressions were triggered the treated cells into CASPASE-3, intrinsic and extrinsic pathways. These findings suggest that the methanol extracts of three parts of A. altilis fruit have potential anticancer activity against MCF-7 cells mainly the pulp part of the fruit.

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Anti-proliferative Effects of Chromones: Potent Derivatives Affecting Cell Growth and Apoptosis in Breast, Bone-marrow and Cervical Cancer Cells

Medicinal Chemistry ◽

10.2174/1573406415666190621155843 ◽

2019 ◽

Vol 15 (8) ◽

pp. 883-891

Author(s):

Syeda Abida Ejaz ◽

Mariia Miliutina ◽

Peter Langer ◽

Aamer Saeed ◽

Jamshed Iqbal

Keyword(s):

Cancer Cells ◽

Chromatin Condensation ◽

Maximum Growth ◽

Future Research ◽

Binding Studies ◽

Proliferative Effect ◽

Cervical Cancer Cells ◽

Apoptotic Effect ◽

K 562 Cells ◽

Mcf 7

Background: Previously, we have identified 3,3′–carbonyl–bis(chromones) (1a-h, 5e) and 3–(5–(benzylideneamino)thiozol–3–yl)–2H–chromen–2–ones (7a-j) as potent inhibitors of tissue non-specific alkaline phosphatase (TNAP). The present study was designed to investigate the cytotoxic and pro-apoptotic effect of the said derivatives. Methods: The anti-proliferative effect of the derivatives was investigated in three cancer cell lines i.e., MCF-7, K-562, HeLa and normal BHK21 cells using MTT assay. The pro-apoptotic effect of the most potent derivatives was investigated by using flow cytometry, DAPI and PI staining and DNA binding studies. Results: Among all the screened compounds, 1f, 1d, 1c (from 3,3′–carbonyl–bis(chromones), 7c, 7h and 7i (from 3–(5–(benzylideneamino)thiozol–3–yl)–2H–chromen–2–ones) exhibited remarkable growth inhibitory effects. Compounds 1f and 7c were found to be the most potent cytotoxic derivatives against MCF-7; 1d and 7h inhibited most of the proliferation of K-562 cells, whereas 1c and 7i showed maximum growth inhibition in HeLa cells. The identified compounds exerted lower micromolar potency against the respective cell line with significant selectivity over the normal cells (BHK–21). The identified compounds also induced either G2 or S-phase arrest within the respective cancer cells, chromatin condensation and nuclear fragmentation, as well as maximum interaction with DNA. Conclusions: These results provide evidence that the characteristic chemical features of attached groups are the key factors for their anticancer effects and play a useful role in revealing the mechanisms of action in relation to the known compounds in future research programs.

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Pyrrolizines as Potential Anticancer Agents: Design, Synthesis, Caspase-3 activation and Micronucleus (MN) Induction

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180409155520 ◽

2019 ◽

Vol 18 (15) ◽

pp. 2124-2130

Author(s):

Amany Belal

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Anticancer Agents ◽

Caspase 3 ◽

Assay Method ◽

Breast Adenocarcinoma ◽

Compound I ◽

Design Synthesis ◽

Ic50 Values ◽

New Compounds

Background: For further exploration of the promising pyrrolizine scaffold and in continuation of our previous work, that proved the potential anticancer activity of the hit compound I, a new series of pyrrolizines 2-5 and 7-9 were designed and synthesized. Methods: Structures of the new compounds were confirmed by IR, 1H-NMR, 13C-NMR and elemental analysis. Antitumor activity for the prepared compounds against human breast adenocarcinoma (MCF-7), liver (HEPG2) and colon (HCT116) cancer cell lines was evaluated using SRB assay method. Result: Compounds 2, 3 and 5 were the most potent on colon cancer cells, their IC50 values were less than 5 µM. Compounds 2, 3 and 8 were the most potent on liver cancer cells, their IC50 values were less than 10 µM. As for MCF7, compounds 2, 7, 8 and 9 were the most active with IC50 values less than 10 µM. We can conclude that combining pyrrolizine scaffold with urea gave abroad spectrum anticancer agent 2 against the three tested cell lines. Micronucleus assays showed that compounds 2, 3, 8 are mutagenic and can induce apoptosis. In addition, caspase-3 activation was evaluated and compound 2 showed increase in the level of caspase-3 (9 folds) followed by 3 (8.28 folds) then 8 (7.89 folds). Conclusion: The obtained results encourage considering these three compounds as novel anticancer prototypes.

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Mutant p53L194F Harboring Luminal-A Breast Cancer Cells Are Refractory to Apoptosis and Cell Cycle Arrest in Response to MortaparibPlus, a Multimodal Small Molecule Inhibitor

Cancers ◽

10.3390/cancers13123043 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3043

Author(s):

Ahmed Elwakeel ◽

Anissa Nofita Sari ◽

Jaspreet Kaur Dhanjal ◽

Hazna Noor Meidinna ◽

Durai Sundar ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Small Molecule ◽

Breast Cancer Cells ◽

Luminal A ◽

Molecular Analyses ◽

Cycle Arrest ◽

Mcf 7

We previously performed a drug screening to identify a potential inhibitor of mortalin–p53 interaction. In four rounds of screenings based on the shift in mortalin immunostaining pattern from perinuclear to pan-cytoplasmic and nuclear enrichment of p53, we had identified MortaparibPlus (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole) as a novel synthetic small molecule. In order to validate its activity and mechanism of action, we recruited Luminal-A breast cancer cells, MCF-7 (p53wild type) and T47D (p53L194F) and performed extensive biochemical and immunocytochemical analyses. Molecular analyses revealed that MortaparibPlus is capable of abrogating mortalin–p53 interaction in both MCF-7 and T47D cells. Intriguingly, upregulation of transcriptional activation function of p53 (as marked by upregulation of the p53 effector gene—p21WAF1—responsible for cell cycle arrest and apoptosis) was recorded only in MortaparibPlus-treated MCF-7 cells. On the other hand, MortaparibPlus-treated T47D cells exhibited hyperactivation of PARP1 (accumulation of PAR polymer and decrease in ATP levels) as a possible non-p53 tumor suppression program. However, these cells did not show full signs of either apoptosis or PAR-Thanatos. Molecular analyses attributed such a response to the inability of MortaparibPlus to disrupt the AIF–mortalin complexes; hence, AIF did not translocate to the nucleus to induce chromatinolysis and DNA degradation. These data suggested that the cancer cells possessing enriched levels of such complexes may not respond to MortaparibPlus. Taken together, we report the multimodal anticancer potential of MortaparibPlus that warrants further attention in laboratory and clinical studies.

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Induction of apoptosis and cell cycle arrest by chloroform fraction of Juniperus phoenicea and chemical constituents analysis

Open Chemistry ◽

10.1515/chem-2021-0195 ◽

2021 ◽

Vol 19 (1) ◽

pp. 119-127

Author(s):

Ibrahim O. Barnawi ◽

Fahd A. Nasr ◽

Omar M. Noman ◽

Ali S. Alqahtani ◽

Mohammed Al-zharani ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Chloroform Fraction ◽

Active Fraction ◽

Cycle Arrest ◽

Juniperus Phoenicea ◽

Medicinal Properties ◽

Mcf 7

Abstract Different phytochemicals from various plant species exhibit promising medicinal properties against cancer. Juniperus phoenicea is a plant species that has been found to present medicinal properties. Herein, crude extract and fractions of J. phoenicea were examined to determine its anticancer properties against several cancer cells. The active fraction was chosen to assess its activity on cell cycle progression and apoptosis induction by annexin and propidium iodide (PI) biomarkers. Further, phytochemical screening for possible contents of active fraction using gas chromatography–mass spectrometry (GC-MS) analysis was conducted. It was demonstrated that cell proliferation was suppressed, and the MCF-7 cell line was the most sensitive to J. phoenicea chloroform fraction (JPCF), with the IC50 values of 24.5 μg/mL. The anti-proliferation activity of JPCF in MCF-7 cells was linked to the aggregation of cells in the G1 phase, increases in early and late apoptosis as well as necrotic cell death. Contents analysis of JPCF using GC-MS analysis identified 3-methyl-5-(2′,6′,6′-trimethylcyclohex-1′-enyl)-1-penten-3-ol (16.5%), methyl 8-oxooctanoate (15.61%), cubenol (13.48%), and 7-oxabicyclo [2.2.1] heptane (12.14%) as major constituents. Our present study provides clear evidence that J. phoenicea can inhibit cell proliferation, trigger cell cycle arrest, and induce apoptosis in tested cancer cells.

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Oxidative Stress and Apoptotic Responses Elicited by Nostoc-Synthesized Silver Nanoparticles against Different Cancer Cell Lines

Cancers ◽

10.3390/cancers12082099 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2099 ◽

Cited By ~ 3

Author(s):

Reham Samir Hamida ◽

Gadah Albasher ◽

Mashael Mohammed Bin-Meferij

Keyword(s):

Oxidative Stress ◽

Silver Nanoparticles ◽

Cancer Cells ◽

Hepg2 Cells ◽

Caspase 3 ◽

Mammalian Target Of Rapamycin ◽

B Cell Lymphoma ◽

Phosphorylated Akt ◽

Hct 116 ◽

Mcf 7

Green nanoparticles represent a revolution in bionanotechnology, providing opportunities to fight life-threatening diseases, such as cancer, with less risk to the environment and to human health. Here, for the first time, we systematically investigated the anticancer activity and possible mechanism of novel silver nanoparticles (N-SNPs) synthesized by Nostoc Bahar M against the MCF-7 breast cancer cells, HCT-116 colorectal adenocarcinoma cells, and HepG2 liver cancer cells, using cell viability assays, morphological characterization with inverted light and transmission electron microscopy, antioxidants and enzymes (glutathione peroxidase (GPx), glutathione (GSH), adenosine triphosphatase (ATPase), and lactate dehydrogenase (LDH)), and western blotting (protein kinase B (Akt), phosphorylated-Akt (p-Akt), mammalian target of rapamycin (mTOR), B-cell lymphoma 2 (Bcl-2), tumor suppressor (p53), and caspase 3). N-SNPs decreased the viability of MCF-7, HCT-116, and HepG2 cells, with half-maximal inhibitory concentrations of 54, 56, and 80 µg/mL, respectively. They also significantly increased LDH leakage, enhanced oxidative stress via effects on antioxidative markers, and caused metabolic stress by significantly decreasing ATPase levels. N-SNPs caused extensive ultrastructural alterations in cell and nuclear structures, as well as in various organelles. Furthermore, N-SNPs triggered apoptosis via the activation of caspase 3 and p53, and suppressed the mTOR signaling pathway via downregulating apoptosis-evading proteins in MCF-7, HCT-116, and HepG2 cells. Ultrastructural analysis, together with biochemical and molecular analyses, revealed that N-SNPs enhanced apoptosis via the induction of oxidative stress and/or through direct interactions with cellular structures in all tested cells. The cytotoxicity of Nostoc-mediated SNPs represents a new strategy for cancer treatment via targeting various cell death pathways. However, the potential of N-SNPs to be usable and biocompatible anticancer drug will depend on their toxicity against normal cells.

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Differential Mechanisms of Cell Death Induced by HDAC Inhibitor SAHA and MDM2 Inhibitor RG7388 in MCF-7 Cells

Cells ◽

10.3390/cells8010008 ◽

2018 ◽

Vol 8 (1) ◽

pp. 8 ◽

Cited By ~ 5

Author(s):

Umamaheswari Natarajan ◽

Thiagarajan Venkatesan ◽

Vijayaraghavan Radhakrishnan ◽

Shila Samuel ◽

Appu Rathinavelu

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Death ◽

Cancer Cells ◽

Hdac Inhibitor ◽

The Other ◽

Combination Treatments ◽

Cycle Arrest ◽

Anti Cancer ◽

Mcf 7

Gene expression is often altered by epigenetic modifications that can significantly influence the growth ability and progression of cancers. SAHA (Suberoylanilide hydroxamic acid, also known as Vorinostat), a well-known Histone deacetylase (HDAC) inhibitor, can stop cancer growth and metastatic processes through epigenetic alterations. On the other hand, Letrozole is an aromatase inhibitor that can elicit strong anti-cancer effects on breast cancer through direct and indirect mechanisms. A newly developed inhibitor, RG7388 specific for an oncogene-derived protein called MDM2, is in clinical trials for the treatment of various cancers. In this paper, we performed assays to measure the effects of cell cycle arrest resulting from individual drug treatments or combination treatments with SAHA + letrozole and SAHA + RG7388, using the MCF-7 breast cancer cells. When SAHA was used individually, or in combination treatments with RG7388, a significant increase in the cytotoxic effect was obtained. Induction of cell cycle arrest by SAHA in cancer cells was evidenced by elevated p21 protein levels. In addition, SAHA treatment in MCF-7 cells showed significant up-regulation in phospho-RIP3 and MLKL levels. Our results confirmed that cell death caused by SAHA treatment was primarily through the induction of necroptosis. On the other hand, the RG7388 treatment was able to induce apoptosis by elevating BAX levels. It appears that, during combination treatments, with SAHA and RG7388, two parallel pathways might be induced simultaneously, that could lead to increased cancer cell death. SAHA appears to induce cell necroptosis in a p21-dependent manner, and RG7388 seems to induce apoptosis in a p21-independent manner, outlining differential mechanisms of cell death induction. However, further studies are needed to fully understand the intracellular mechanisms that are triggered by these two anti-cancer agents.

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