The Roles of 4β-Hydroxywithanolide E from Physalis peruviana on the Nrf2-Anti-Oxidant System and the Cell Cycle in Breast Cancer Cells

2016 ◽  
Vol 44 (03) ◽  
pp. 617-636 ◽  
Author(s):  
Chieh Yu Peng ◽  
Bang Jau You ◽  
Chia Lin Lee ◽  
Yang Chang Wu ◽  
Wen Hsin Lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
System Response ◽  
Cell Cycle Distribution ◽  
Ros Production ◽  
Cell Cycle Regulators ◽  
Antitumor Effects ◽  
Physalis Peruviana ◽  
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4[Formula: see text]-Hydroxywithanolide E is an active component of the extract of Physalis peruviana that has been reported to exhibit antitumor effects. Although the involvement of reactive oxygen species (ROS) production and the ataxia-telangiectasia mutated protein (ATM)-dependent DNA damage signaling pathway in 4[Formula: see text]-hydroxywithanolide E-induced apoptosis of breast cancer MCF-7 cells was demonstrated in our previous study, the relationship between ROS production and the cellular defense system response in 4[Formula: see text]-hydroxywithanolide E-induced cell death requires further verification. The present study suggests that ROS play an important role in 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in which anti-oxidants, such as glutathione or N-acetylcysteine, can resist the 4[Formula: see text]-hydroxywithanolide E-induced accumulation of ROS and cell death. Furthermore, N-acetylcysteine or glutathione can reverse the 4[Formula: see text]-hydroxywithanolide E-induced changes in the cell cycle distribution and the expression of cell cycle regulators. We found that the 4[Formula: see text]-hydroxywithanolide E-induced ROS accumulation was correlated with the upregulation of Nrf2 and Nrf2-downstream genes, such as antioxidative defense enzymes. In general, the activity of Nrf2 is regulated by the Ras signalling pathway. However, we demonstrated that Nrf2 was activated during 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in spite of the 4[Formula: see text]-hydroxywithanolide E-induced inhibition of the Ras/Raf/ERK pathway. The activity and protein expression of superoxide dismutase and catalase were involved in the 4[Formula: see text]-hydroxywithanolide E-induced ROS production in MCF-7 cells. Furthermore, 4[Formula: see text]-hydroxywithanolide E was demonstrated to significantly reduce the sizes of the tumor nodules in the human breast cancer MDA-MB231 xenograft tumor model.

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

Cells ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 8 ◽  
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 ◽  
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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.

Patterns of Cell Death Induced by Thiohydantoins in Human MCF-7 Breast Cancer Cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Tatiane Renata Fagundes ◽  
Bruna Bortoleti ◽  
Priscila Camargo ◽  
Vírgínia Concato ◽  
Fernanda Tomiotto-Pellissier ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Volume ◽  
Tumor Cells ◽  
Breast Tumor ◽  
Breast Cancer Cells ◽  
Breast Tumor Cells ◽  
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Background: Conventional therapies for breast cancer is still a challenge due to use of cytotoxic drugs not highly effective with major adverse effects. Thiohydantoins, are biologically active heterocyclic compounds reported by several biological activities, including anticarcinogenic properties, i.e., this work aimed to assess the use of thiohydantoin as a potential antitumor agent against MCF-7 breast cancer cells. Methods: MTT and neutral red assays were used to assess the possible cytotoxic activity of compounds against MCF-7 cells. Cell volume measurement and analysis were performed by flow cytometry, fluorescence analysis was carried out to determine patterns of cell death induced by thiohydantoins. Results: The treatment with micromolar doses of thiohydantoins promoted a decrease in the viability of MCF-7 breast tumor cells. Also were observed the increase in ROS and NO production, reduction in cell volume, loss of membrane integrity, mitochondrial depolarization, and increased fluorescence for annexin V and caspase-3. These findings indicate cell death by apoptosis and increased formation of autophagic vacuoles and stopping the cell cycle in the G1/ G0 phase. Conclusions: Our results indicate that thiohydantoins are cytotoxic to breast tumor cells, and this effect is linked to the increase in ROS production. This phenomenon changes tumorigenic pathways, that lead to a halt of the cell cycle in G1/G0, an important checkpoint for DNA errors, which may have altered the process by which cells produce energy, causing a decrease in mitochondrial viability and thus leading to the apoptotic process. Furthermore, the results indicate increased autophagy, a vital process linked to a decrease in lysosomal viability and considered as a cell death and tumor suppression mechanism.

Targeting Cell Necroptosis and Apoptosis Induced by Shikonin via Receptor Interacting Protein Kinases in Estrogen Receptor Positive Breast Cancer Cell Line, MCF-7

2018 ◽  
Vol 18 (2) ◽  
pp. 245-254 ◽  
Author(s):  
Zahra Shahsavari ◽  
Fatemeh Karami-Tehrani ◽  
Siamak Salami
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
Membrane Potential ◽  
Cell Line ◽  
Mitochondrial Membrane Potential ◽  
Breast Cancer Cell Line ◽  
Mitochondrial Membrane ◽  
Cancer Cell Line ◽  
Mcf 7

Background: Recognition of a new therapeutic agent may activate an alternative programmed cell death for the treatment of breast cancer. Objective: Here, it has been tried to evaluate the effects of Shikonin, a naphthoquinone derivative of Lithospermum erythrorhizon, on the induction of necroptosis and apoptosis mediated by RIPK1-RIPK3 in the ER+ breast cancer cell line, MCF-7. Methods: In the current study, cell death modalities, cell cycle patterns, RIPK1 and RIPK3 expressions, caspase-3 and caspase-8 activities, reactive oxygen species and mitochondrial membrane potential have been evaluated in the Shikonin-treated MCF-7 cells. Results: Necroptosis and apoptosis have been occurred by Shikonin, with a significant increase in RIPK1 and RIPK3 expressions, although necroptosis was the major rout in MCF-7 cells. Shikonin significantly increased the percentage of the cells in sub-G1 and also those in the later stages of cell cycle, which represents an increase in necroptosis and apoptosis. Under caspase inhibition by Z-VAD-FMK, Shikonin has stimulated necroptosis, which could be arrested by Nec-1. An increase in ROS levels and a decrease in the mitochondrial membrane potential have also been observed. Conclusion: On the basis of present findings, Shikonin has been suggested as a good candidate for the induction of cell death in ER+ breast cancer, although further investigations, experimental and clinical, are required.

Evaluation of Cytotoxic Mechanisms of Clinacanthus Nutans Extracts in Cancer Cells

2020 ◽  
Vol 10 ◽  
Author(s):  
Nurul Atiqah Sulaiman ◽  
Rajan Rajabalaya ◽  
Shirley Huan Fang Lee ◽  
Ya Chee Lim ◽  
Wei Hon Lim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Flow Cytometry ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Annexin V ◽  
Cell Cycle Profile ◽  
Clinacanthus Nutans ◽  
Mcf 7

Background: Commercially available Clinacanthus nutans (Burm.F) Lindau (Acanthaceae) (CN) leaf preparations are gaining attention as an alternative cancer treatment, particularly in South East Asia. Multiple studies have suggested that CN has potential anticancer activities; however, the mechanism of these activities has remained elusive. Objective: This study evaluated the cytotoxic mechanisms of CN extracts in cancer cells. Methods: CN extracts were prepared from either fresh or dried leaves, using different solvents. Cytotoxicity of CN extracts were tested on the A549 (lung cancer), HeLa (cervical cancer), MCF-7 (breast cancer) and MDA-MB-231 (breast cancer) cell lines using the MTT assay. Flow cytometry was used to assess changes in the cell cycle profile, while Western blotting was used to examine microtubule stability. Finally, the mode of cell death was investigated using the Annexin V-FITC Apoptosis Detection Kit. Results: Aqueous Fresh (AQF) extract was prepared to simulate the ethno-medicinal use of CN, and reduced cell viability of MCF-7 cells with IC50 = 1.71 mg/mL. Some CN extracts have the ability to inhibit the proliferation of four different cancer cell lines after a 24 hour treatment. Annexin V assay results shows that acetone extracts of CN induced increments in percentage of apoptotic cell death. However, flow cytometry results show that cancer cell cycle profile were not affected. Similarly, immunoblotting results also indicate that microtubule dynamics in MCF-7 cells were not altered. However, the aqueous extract, prepared to simulate the current ethnomedicinal use of CN leaves in cancer treatment, did not significantly inhibit cancer cell proliferation with IC50 = 1.71 mg/mL. Conclusions: This study was the first to show that microtubules in cancer cells remain dynamic after treatment with CN extracts, effectively ruling interference of microtubule dynamics as the mode of cell death. AMD extract showed the highest effects MCF-7 cell proliferation.

The antitumor effects of icaritin against breast cancer is related to estrogen receptors

2020 ◽  
Vol 20 ◽  
Author(s):  
Cheng-Cheng Tao ◽  
Yue Wu ◽  
Xiang Gao ◽  
Ling Qiao ◽  
Ying Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Western Blotting ◽  
Proliferation Inhibition ◽  
Antitumor Effects ◽  
Autophagy Inhibitor ◽  
And Migration ◽  
Induced Apoptosis ◽  
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Proliferation And Migration

Objective: We aim to investigate the anticancer effects and mechanisms of icaritin against breast cancer. Materials and Methods: Both estrogen receptor (ER) positive breast cancer cells MCF-7 and ER-negative MDA-MB-231 cells were employed. We examined the effects of icaritin on the proliferation and migration by wound healing assay and transwell assay. Cell apoptosis and cell cycle of MCF-7 and MDA-MB-231 cells were analyzed using Flow cytometry. Cell autophagy of MCF-7 and MDA-MB-231 cells was assessed by western blotting, acridine orange staining and confocal microscopy. We also detected the expression of apoptosis related genes by western blotting. In addition, an autophagy inhibitor was used to investigate whether cytoprotective autophagy was induced. Meanwhile, an ER inhibitor was utilized to explore whether ER was involved in autophagy. Results: Icaritin inhibited the proliferation and migration, and induced cell cycle arrest of both MDA-MB-231 and MCF7 cells. Icaritin significantly induced apoptosis of MDA-MB-231 cells by activating caspase-3. And icaritin stimulated autophagy in MCF-7 cells, as evidenced by increased LC3II/LC3I, enhanced p62 degradation, the accumulation of endogenous LC3 puncta formation, and the increased autophagy flux. Icaritin induced autophagy through upregulating the phosphorylation of AMPK and ULK1. Chloroquine, an autophagy inhibitor, increased icaritin-induced apoptosis and proliferation inhibition of MCF-7 cells. Meanwhile, tamoxifen, an ER inhibitor, reversed icaritin-induced autophagy and proliferation inhibition of MCF-7 cells. Conclusion: Our study demonstrated that the antitumor effects of icaritin against breast cancer are related with ER, which suggested that the status of ER should be considered in clinical application of icaritin.

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