Physiological Concentrations of Ascorbic Acid Potentiate Cell Death by Hydrogen Peroxide and Nitric Oxide of Non-Attached Cancer Cell Lines for the Possible Clearance of Cancer Cells from the Microcirculation

Background: Natural product with apoptotic activity could serve as a potential new source for anti-cancer medicine. Numerous phytochemicals from plants have shown to exert antineoplastic effects via programmed cell death (apoptosis). Cancer is one of the leading causes of death in prosperous countries. The subject study was intended to evaluate the anticancer properties of Kalonji extracts against cancer cell lines HeLa and HepG2 and normal cell lines BHK and VERO were used as normal controls. Materials & Methods: For the evaluation of anti-proliferative effects, cell viability and cell death in all groups of cells were evaluated via MTT, crystal violet and trypan blue assays. For the evaluation of angiogenesis, Immunocytochemistry and ELISA of VEGF were done. Immunocytochemistry and ELISA of Annexin-V and p53 were performed for the estimation of apoptosis in all groups of cells. Furthermore, LDH assay, antioxidant enzymes activity (GSH, APOX, CAT and SOD) and RT-PCR with proliferative and apoptotic markers along with internal control were also performed. Cancer cells of both cell lines HepG2 and HeLa cells showed reduced viability, angiogenesis and proliferation with increased apoptosis when treated with Kalonji extracts. Whereas anti-oxidative enzymes show enhanced levels in treated cancer cells as compared to untreated ones. Conclusion: It was observed that Kalonji extracts have the ability to induce apoptosis and improve the antioxidant status of HeLa and HepG2 cells. They can also inhibit the proliferation and angiogenesis in both these cancer cell lines.

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Clinacanthus nutansExtracts Are Antioxidant with Antiproliferative Effect on Cultured Human Cancer Cell Lines

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/462751 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 45

Author(s):

Yoke Keong Yong ◽

Jun Jie Tan ◽

Soek Sin Teh ◽

Siau Hui Mah ◽

Gwendoline Cheng Lian Ee ◽

...

Keyword(s):

Nitric Oxide ◽

Hydrogen Peroxide ◽

Cancer Prevention ◽

Cell Lines ◽

Cancer Cell ◽

Raji Cell ◽

Cancer Cell Lines ◽

Chloroform Extract ◽

Antiproliferative Effect ◽

Dependent Manner

Clinacanthus nutansLindau leaves (CN) have been used in traditional medicine but the therapeutic potential has not been explored for cancer prevention and treatment. Current study aimed to evaluate the antioxidant and antiproliferative effects of CN, extracted in chloroform, methanol, and water, on cancer cell lines. Antioxidant properties of CN were evaluated using DPPH, galvinoxyl, nitric oxide, and hydrogen peroxide based radical scavenging assays, whereas the tumoricidal effect was tested on HepG2, IMR32, NCL-H23, SNU-1, Hela, LS-174T, K562, Raji, and IMR32 cancer cells using MTT assay. Our data showed that CN in chloroform extract was a good antioxidant against DPPH and galvinoxyl radicals, but less effective in negating nitric oxide and hydrogen peroxide radicals. Chloroform extract exerted the highest antiproliferative effect on K-562 (91.28±0.03%) and Raji cell lines (88.97±1.07%) at 100 μg/ml and the other five cancer cell lines in a concentration-dependent manner, but not on IMR-32 cells. Fourteen known compounds were identified in chloroform extract, which was analysed by gas chromatography—mass spectra analysis. In conclusion, CN extracts possess antioxidant and antiproliferative properties against cultured cancer cell lines, suggesting an alternate adjunctive regimen for cancer prevention or treatment.

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Time to tame necroptosis - viable combat against chemo resistant oral cancer cells

Oncology Reviews ◽

10.4081/oncol.2018.358 ◽

2018 ◽

Author(s):

Samapika Routray

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Cell Lines ◽

Anticancer Drugs ◽

Cancer Cell ◽

Alternative Pathway ◽

Cancer Cell Lines ◽

Tanshinone Iia ◽

Death Domain ◽

Naturally Occurring

Till 1998, a little was known about alternative forms of regulated cell death beside apoptosis. In present scenario, accumulating evidences suggest a form of programmed necrosis called Necroptosis which can be induced by various external stimuli including anticancer drugs, ionizing radiation, photodynamic therapy in the form of death domain receptor (DR) engagement by their respective ligands, TNF-alpha, Fas ligand (FasL) and TRAIL, under apoptosis deficient condition (caspase inhibitor), etc. receptor interacting protein-1 (RIP-1), a death domain containing kinase is the key molecule in necroptotic cell death pathway. On interaction with an additional protein RIP-3 to form an intracellular complex (complex-IIb), it triggers the various downstream mechanisms of necroptosis which includes: i) excessive production reactive oxygen species (ROS) as RIP-3 interacts with metabolic enzymes (glycogen phosphorylase, glutamate dehydrogenase) which increases the concentration of substrates for oxidative phophorylation - a major source of ROS; ii) mitochondrial dysfunction (mitrochondrial permeability transition ). Necrostatin (Nec-1) and CYLD act as negative and positive regulators for this mode of cell death.TNF the master pro-inflammatory cytokine has been known to either promote gene activation or to induce RIPK1 kinase-dependent cell death, in the form of apoptosis or necroptosis. Autophagy has also been proposed as an execution mechanism for necroptosis. There is growing evidence of impairment of necroptosis in tumerogenesis of various human cancers such as chronic lymphocytic leukemia, epidermal cancer and non Hodgkins lymphoma.As conventional anticancer drugs are usually apoptosis inducers, the development of apoptosis resistant cell clones is inevitable owing to cancer heterogeneity and mutation leading to failure of standard chemotherapy. It is a known fact that triggering necroptosis could be an alternative way to eradicate apoptosis-resistant cancer cells. Development of a new class of anticancer drug targeting this alternative pathway of the cell death is the need of the hour. Few in vitro and in vivo studies have been conducted showing excellent anti-tumor effect in both drug sensitive and resistant cases by targeting different modulators of necroptotic pathway: i) shikonin-a naturally occurring naphthoquinone showed prompt but profound anti-tumor effect on both primary and metastatic tumor i.e. cancer cell lines and osteosarcoma by inducing RIPK1 and RIPK3 dependent necroptosis; ii) staurosporine-generally accepted inducer of intrinsic apoptotic pathway and it is a wide spectrum inhibitor of protein kinases. It can induce necroptosis in caspase compromised conditions; iii) deoxypodophyllotoxin - a naturally occurring microtubule destabilizer successfully induced necroptosis in both drug sensitive and drug resistant cancer cell lines; iv) targeting Nec-1, a specific inhibitor of necroptosis can help in inducing necroptosis to enhance the radiosensitivity of cancer cells. Tanshinone IIA (Tan IIA) is known to induces both Nec-1 inhibition and FLIPS regulation-mediated apoptosis/necroptosis; v) obatoclax induces the interaction of p62 with RIP1K, RIP3K and FADD, key components of the necrosome and can mediate cell death in oral squamous cell carcinoma (OSCC) cells via autophagy-dependent necroptosis.Despite the rigorous implement of conventional therapies, increased number of refractory cases is unavoidable due to acquired resistance of cancer cells, badly affecting survival rate of OSCC. Additional knowledge about the mechanisms of cancer drug resistance and development of novel targeted therapy using alternative pathway of cell death and less susceptible to known resistance mechanisms i.e. necroptosis-based cancer therapy may help in designing effective anticancer strategies for OSCC .

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The Azurin-Derived Peptide CT-p19LC Exhibits Membrane-Active Properties and Induces Cancer Cell Death

Biomedicines ◽

10.3390/biomedicines9091194 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1194

Author(s):

Ana Rita Garizo ◽

Lígia F. Coelho ◽

Sandra Pinto ◽

Tiago P. Dias ◽

Fábio Fernandes ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Total Charge ◽

Cancer Cell Death ◽

Proliferation And Apoptosis ◽

Mcf 7

Peptides have been thoroughly studied as new therapeutic strategies for cancer treatment. In this work, we explored in vitro the anticancer potential of three novel peptides derived from the C-terminal of azurin, an anticancer bacterial protein produced by Pseudomonas aeruginosa. CT-p26, CT-p19 and CT-p19LC peptides were previously obtained through an in silico peptide design optimization process, CT-p19LC being the most promising as it presented higher hydrophobicity and solubility, positive total charge and, most importantly, greater propensity for anticancer activity. Therefore, in this study, through proliferation and apoptosis assays, CT-p19LC was tested in four cancer cell lines—A549, MCF-7, HeLa and HT-29—and in two non-cancer cell lines—16HBE14o- and MCF10A. Its membrane-targeting activity was further evaluated with zeta potential measurements and membrane order was assessed with the Laurdan probe. The results obtained demonstrated that CT-p19LC decreases cell viability through induction of cell death and binds to the plasma membrane of cancer cells, but not to non-cancer cells, making them less rigid. Overall, this study reveals that CT-p19LC is an auspicious selective anticancer peptide able to react with cancer cell membranes and cause effective action.

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Synthesis and Characterization of Quinoline-3-Carboxamide Derivatives as Inhibitors of the ATM Kinase

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200731174216 ◽

2020 ◽

Vol 20 (23) ◽

pp. 2070-2079

Author(s):

Srimadhavi Ravi ◽

Sugata Barui ◽

Sivapriya Kirubakaran ◽

Parul Duhan ◽

Kaushik Bhowmik

Keyword(s):

Western Blot ◽

Cancer Cells ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Blot Analysis ◽

Western Blot Analysis ◽

Cancer Cell Lines ◽

Atm Kinase ◽

Cytotoxicity Studies

Background: The importance of inhibiting the kinases of the DDR pathway for radiosensitizing cancer cells is well established. Cancer cells exploit these kinases for their survival, which leads to the development of resistance towards DNA damaging therapeutics. Objective: In this article, the focus is on targeting the key mediator of the DDR pathway, the ATM kinase. A new set of quinoline-3-carboxamides, as potential inhibitors of ATM, is reported. Methods: Quinoline-3-carboxamide derivatives were synthesized and cytotoxicity assay was performed to analyze the effect of molecules on different cancer cell lines like HCT116, MDA-MB-468, and MDA-MB-231. Results: Three of the synthesized compounds showed promising cytotoxicity towards a selected set of cancer cell lines. Western Blot analysis was also performed by pre-treating the cells with quercetin, a known ATM upregulator, by causing DNA double-strand breaks. SAR studies suggested the importance of the electron-donating nature of the R group for the molecule to be toxic. Finally, Western-Blot analysis confirmed the down-regulation of ATM in the cells. Additionally, the PTEN negative cell line, MDA-MB-468, was more sensitive towards the compounds in comparison with the PTEN positive cell line, MDA-MB-231. Cytotoxicity studies against 293T cells showed that the compounds were at least three times less toxic when compared with HCT116. Conclusion: In conclusion, these experiments will lay the groundwork for the evolution of potent and selective ATM inhibitors for the radio- and chemo-sensitization of cancer cells.

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Design, Synthesis and Biological Evaluation: 5-amino-1H-pyrazole-1- carbonyl derivatives as FGFR Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180817999200608140628 ◽

2020 ◽

Vol 17 (11) ◽

pp. 1330-1341

Author(s):

Yan Zhang ◽

Niefang Yu

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Biological Evaluation ◽

Human Gastric Cancer ◽

Design Synthesis ◽

Carbonyl Derivatives ◽

Ic50 Values ◽

Inhibitory Activities

Background: Fibroblast growth factors (FGFs) and their high affinity receptors (FGFRs) play a major role in cell proliferation, differentiation, migration, and apoptosis. Aberrant FGFR signaling pathway might accelerate development in a broad panel of malignant solid tumors. However, the full application of most existing small molecule FGFR inhibitors has become a challenge due to the potential target mutation. Hence, it has attracted a great deal of attention from both academic and industrial fields for hunting for novel FGFR inhibitors with potent inhibitory activities and high selectivity. Objective: Novel 5-amino-1H-pyrazole-1-carbonyl derivatives were designed, synthesized, and evaluated as FGFR inhibitors. Methods: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives were established by a condensation of the suitable formyl acetonitrile derivatives with either hydrazine or hydrazide derivatives in the presence of anhydrous ethanol or toluene. The inhibitory activities of the target compounds were screened against the FGFRs and two representative cancer cell lines. Tests were carried out to observe the inhibition of 8e against FGFR phosphorylation and downstream signal phosphorylation in human gastric cancer cell lines (SNU-16). The molecular docking of all the compounds were performed using Molecular Operating Environment in order to evaluate their binding abilities with the corresponding protein kinase. Results: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives have been designed and synthesized, screened for their inhibitory activities against FGFRs and cancer cell lines. Most of the target compounds showed moderate to good anti-proliferate activities against the tested enzymes and cell lines. The most promising compounds 8e suppressed FGFR1-3 with IC50 values of 56.4, 35.2, 95.5 nM, and potently inhibited the SNU-16 and MCF-7 cancer cells with IC50 values of 0.71 1.26 μM, respectively. And 8e inhibited the growth of cancer cells containing FGFR activated by multiple mechanisms. In addition, the binding interactions were quite similar in the molecular models between generated compounds and Debio-1347 with the FGFR1. Conclusion: According to the experimental findings, 5-amino-1H-pyrazole-1-carbonyl might serve as a promising template of an FGFR inhibitor.

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Small Molecular Leads Differentially Active Against HER2 Positive and Triple Negative Breast Cancer Cell Lines

Medicinal Chemistry ◽

10.2174/1573406414666181106143912 ◽

2019 ◽

Vol 15 (7) ◽

pp. 738-742 ◽

Cited By ~ 1

Author(s):

Adnan Badran ◽

Atia-tul-Wahab ◽

Sharmeen Fayyaz ◽

Elias Baydoun ◽

Muhammad Iqbal Choudhary

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Triple Negative ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines ◽

Cancer Type

Background:Breast cancer is the most prevalent cancer type in women globally. It is characterized by distinct subtypes depending on different gene expression patterns. Oncogene HER2 is expressed on the surface of cell and is responsible for cell growth regulation. Increase in HER2 receptor protein due to gene amplification, results in aggressive growth, and high metastasis in cancer cells.Methods:The current study evaluates and compares the anti-breast cancer effect of commercially available compounds against HER2 overexpressing BT-474, and triple negative MDA-MB-231 breast cancer cell lines.Results:Preliminary in vitro cell viability assays on these cell lines identified 6 lead molecules active against breast cancer. Convallatoxin (4), a steroidal lactone glycoside, showed the most potent activity with IC50 values of 0.63 ± 0.56, and 0.69 ± 0.59 µM against BT-474 and MDA-MB-231, respectively, whereas 4-[4-(Trifluoromethyl)-phenoxy] phenol (3) a phenol derivative, and Reserpine (5) an indole alkaloid selectively inhibited the growth of BT-474, and MDA-MB-231 breast cancer cells, respectively.Conclusion:These results exhibited the potential of small molecules in the treatment of HER2 amplified and triple negative breast cancers in vitro.

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Antiplatelet Therapy Combined with Anastrozole Induces Features of Partial EMT in Breast Cancer Cells and Fails to Mitigate Breast-Cancer Induced Hypercoagulation

International Journal of Molecular Sciences ◽

10.3390/ijms22084153 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4153

Author(s):

Kutlwano R. Xulu ◽

Tanya N. Augustine

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Antiplatelet Therapy ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cells ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines

Thromboembolic complications are a leading cause of morbidity and mortality in cancer patients. Cancer patients often present with an increased risk for thrombosis including hypercoagulation, so the application of antiplatelet strategies to oncology warrants further investigation. This study investigated the effects of anastrozole and antiplatelet therapy (aspirin/clopidogrel cocktail or atopaxar) treatment on the tumour responses of luminal phenotype breast cancer cells and induced hypercoagulation. Ethical clearance was obtained (M150263). Blood was co-cultured with breast cancer cell lines (MCF7 and T47D) pre-treated with anastrozole and/or antiplatelet drugs for 24 h. Hypercoagulation was indicated by thrombin production and platelet activation (morphological and molecular). Gene expression associated with the epithelial-to-mesenchymal transition (EMT) was assessed in breast cancer cells, and secreted cytokines associated with tumour progression were evaluated. Data were analysed with the PAST3 software. Our findings showed that antiplatelet therapies (aspirin/clopidogrel cocktail and atopaxar) combined with anastrozole failed to prevent hypercoagulation and induced evidence of a partial EMT. Differences in tumour responses that modulate tumour aggression were noted between breast cancer cell lines, and this may be an important consideration in the clinical management of subphenotypes of luminal phenotype breast cancer. Further investigation is needed before this treatment modality (combined hormone and antiplatelet therapy) can be considered for managing tumour associated-thromboembolic disorder.

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Super Magnetic Niosomal Nanocarrier as a New Approach for Treatment of Breast Cancer: A Case Study on SK-BR-3 and MDA-MB-231 Cell Lines

International Journal of Molecular Sciences ◽

10.3390/ijms22157948 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7948

Author(s):

Elham Jamshidifar ◽

Faten Eshrati Yeganeh ◽

Mona Shayan ◽

Mohammad Tavakkoli Yaraki ◽

Mahsa Bourbour ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Cellular Uptake ◽

Targeted Delivery ◽

Breast Cancer Cells ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines ◽

Silica Layer

In the present study, a magnetic niosomal nanocarrier for co-delivery of curcumin and letrozole into breast cancer cells has been designed. The magnetic NiCoFe2O4 core was coated by a thin layer of silica, followed by a niosomal structure, allowing us to load letrozole and curcumin into the silica layer and niosomal layer, respectively, and investigate their synergic effects on breast cancer cells. Furthermore, the nanocarriers demonstrated a pH-dependent release due to the niosomal structure at their outer layer, which is a promising behavior for cancer treatment. Additionally, cellular assays revealed that the nanocarriers had low cellular uptake in the case of non-tumorigenic cells (i.e., MCF-10A) and related high viability but high cellular uptake in cancer cell lines (i.e., MDA-MB-231 and SK-BR-3) and related low viability, which is evidenced in their high cytotoxicity against different breast cancer cell lines. The cytotoxicity of the letrozole/curcumin co-loaded nanocarrier is higher than that of the aqueous solutions of both drugs, indicating their enhanced cellular uptake in their encapsulated states. In particular, NiCoFe2O4@L-Silica-L@C-Niosome showed the highest cytotoxicity effects on MDA-MB-231 and SK-BR-3 breast cancer cells. The observed cytotoxicity was due to regulation of the expression levels of the studied genes in breast cancer cells, where downregulation was observed for the Bcl-2, MMP 2, MMP 9, cyclin D, and cyclin E genes while upregulation of the expression of the Bax, caspase-3, and caspase-9 genes was observed. The flow cytometry results also revealed that NiCoFe2O4@L-Silica-L@C-Niosome enhanced the apoptosis rate in both MDA-MB-231 and SK-BR-3 cells compared to the control samples. The findings of our research show the potential of designing magnetic niosomal formulations for simultaneous targeted delivery of both hydrophobic and hydrophilic drugs into cancer cells in order to enhance their synergic chemotherapeutic effects. These results could open new avenues into the future of nanomedicine and the development of theranostic agents.

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