Abstract 4372: Effects of high glucose and DCA on ROS production and viability of breast cancer cells with disrupted antioxidant systems

Bioactive compounds from plants represent good candidate drugs for the prevention and treatment of various forms of cancer. Berries are rich sources of bioactive compounds, and there has been an increasing interest in the study of therapeutic action of wild berries. Oxidants are generated continuously in biological system as a result of physiological process. When there is an imbalance between oxidants and antioxidants, it leads to a condition called oxidative stress. Natural compounds as inducers of oxidative stress are able to modulate the physiological functions of cancer cells leading to cell death or survival. The aim of this study was to evaluate the induction of apoptosis by isolated bioactive compounds (1-(2-hydroxyphenyl)-4-methylpentan-1-one (C1) and 2-[(3-methylbutoxy) carbonyl] benzoic acid (C2)) from Rubus fairholmianus against MCF-7 breast cancer cells. The exposure of C1 and C2 reduced viability (IC50 of C1: 4.69; C2: 8.36 μg/mL) and proliferation. Cytochrome c release from mitochondria and changes in mitochondrial membrane potential of treated cells supported the intrinsic apoptotic cell death. Reactive oxygen species (ROS) production after treatment with C1 and C2 was found to be higher and induced nuclear damage. Expression of apoptotic proteins after the treatments was significantly upregulated as indicated using immunofluorescence (caspase 9, p53, and Bax), western blotting (p53, cleaved PARP, cytochrome c, and Bax), and ELISA (caspase 9) analysis. Overall, C1 was more cytotoxic, increased the ROS production in dichlorodihydrofluorescein diacetate assay, and induced apoptosis in breast cancer cells. These results illustrate that berry bioactive compounds have strong chemopreventive potential. In this article, we provide information on prooxidant and anticancer activities of Rubus bioactive compounds. Natural products have always demonstrated a significant contribution to the development of several cancer chemotherapeutic drugs. Most of these compounds are known to affect the redox state of the cell; and studies on these compounds have focused on their antioxidant property instead of prooxidant properties.

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NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21207802 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7802 ◽

Cited By ~ 1

Author(s):

Vincenzo Quagliariello ◽

Michelino De Laurentiis ◽

Stefania Cocco ◽

Giuseppina Rea ◽

Annamaria Bonelli ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Triple Negative Breast Cancer ◽

High Glucose ◽

Breast Cancer Cells ◽

Triple Negative ◽

Anticancer Efficacy ◽

Low Glucose ◽

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Hyperglycemia, obesity and metabolic syndrome are negative prognostic factors in breast cancer patients. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, achieving unprecedented efficacy in multiple malignancies. However, ICIs are associated with immune-related adverse events involving cardiotoxicity. We aimed to study if hyperglycemia could affect ipilimumab-induced anticancer efficacy and enhance its cardiotoxicity. Human cardiomyocytes and estrogen-responsive and triple-negative breast cancer cells (MCF-7 and MDA-MB-231 cell lines) were exposed to ipilimumab under high glucose (25 mM); low glucose (5.5 mM); high glucose and co-administration of SGLT-2 inhibitor (empagliflozin); shifting from high glucose to low glucose. Study of cell viability and the expression of new putative biomarkers of cardiotoxicity and resistance to ICIs (NLRP3, MyD88, cytokines) were quantified through ELISA (Cayman Chemical) methods. Hyperglycemia during treatment with ipilimumab increased cardiotoxicity and reduced mortality of breast cancer cells in a manner that is sensitive to NLRP3. Notably, treatment with ipilimumab and empagliflozin under high glucose or shifting from high glucose to low glucose reduced significantly the magnitude of the effects, increasing responsiveness to ipilimumab and reducing cardiotoxicity. To our knowledge, this is the first evidence that hyperglycemia exacerbates ipilimumab-induced cardiotoxicity and decreases its anticancer efficacy in MCF-7 and MDA-MB-231 cells. This study sets the stage for further tests on other breast cancer cell lines and primary cardiomyocytes and for preclinical trials in mice aimed to decrease glucose through nutritional interventions or administration of gliflozines during treatment with ipilimumab.

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SIRT3 Silencing Sensitizes Breast Cancer Cells to Cytotoxic Treatments Through an Increment in ROS Production

Journal of Cellular Biochemistry ◽

10.1002/jcb.25653 ◽

2016 ◽

Vol 118 (2) ◽

pp. 397-406 ◽

Cited By ~ 26

Author(s):

Margalida Torrens-Mas ◽

Daniel Gabriel Pons ◽

Jorge Sastre-Serra ◽

Jordi Oliver ◽

Pilar Roca

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Ros Production

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High glucose levels promote the proliferation of breast cancer cells through GTPases

Breast Cancer Targets and Therapy ◽

10.2147/bctt.s135665 ◽

2017 ◽

Vol Volume 9 ◽

pp. 429-436 ◽

Cited By ~ 12

Author(s):

Yilin Hou ◽

Man Zhou ◽

Jing Xie ◽

Ping Chao ◽

Qiyu Feng ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

High Glucose ◽

Breast Cancer Cells ◽

Glucose Levels

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Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-α and PPAR expression

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/s0167-4889(02)00276-8 ◽

2002 ◽

Vol 1592 (2) ◽

pp. 107-116 ◽

Cited By ~ 126

Author(s):

Mie Okumura ◽

Mayumi Yamamoto ◽

Hiroya Sakuma ◽

Toshihiro Kojima ◽

Takako Maruyama ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

High Glucose ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Stimulate Cell Proliferation ◽

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The Effect of a Newly Synthesized Ferrocene Derivative against MCF-7 Breast Cancer Cells and Spheroid Stem Cells through ROS Production and Inhibition of JAK2/STAT3 Signaling Pathway

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200101151743 ◽

2020 ◽

Vol 20 (7) ◽

pp. 875-886 ◽

Cited By ~ 1

Author(s):

Mitra Nourbakhsh ◽

Shabnam Farzaneh ◽

Adeleh Taghikhani ◽

Afshin Zarghi ◽

Shokoofe Noori

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Flow Cytometry ◽

Stem Cell ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tetrazolium Salt ◽

Ros Production ◽

Expression Of Genes ◽

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Background: Breast Cancer Stem Cells (BCSCs) possess the ability of self-renewal and cellular heterogeneity, and therefore, play a key role in the initiation, propagation and clinical outcome of breast cancer. It has been shown that ferrocene complexes have remarkable potential as anticancer drugs. Objective: The present study was conducted to investigate the effects of a novel ferrocene complex, 1- ferrocenyl-3-(4-methylsulfonylphenyl)propen-1-one (FMSP) on MCF-7 breast cancer cell line and its derived mammospheres with cancer stem cell properties. Methods: Mammospheres were developed from MCF-7 cells and validated by the evaluation of CD44 and CD24 cell surface markers by flow cytometry as well as of the expression of genes that are associated with stem cell properties by real-time PCR. Cells viability was assessed by a soluble tetrazolium salt (MTS) after the treatment of cells with various concentrations of FMSP. Apoptosis was evaluated by flow cytometry analysis of annexin V and PI labeling of cells. Reactive Oxygen Species (ROS) production was measured using a cellpermeable, oxidant-sensitive fluorescence probe (carboxy-H2DCFDA). The involvement of the JAK2/STAT3 pathway was also investigated by western blotting. Results: FMSP could successfully prevent mammosphere formation from differentiated MCF-7 cells and significantly down-regulated the expression of genes involved in the production of the stem cell properties including Wnt1, Notch1, β -catenin, SOX2, CXCR4 and ALDH1A1. FMSP decreased cell viability in both MCF-7 cells and spheroid cells, although MCF-10A cells were unaffected by this compound. Apoptosis was also dramatically induced by FMSP, via ROS production but independent of CD95 activation. Phosphorylation levels of JAK2 and STAT3 were also found to be significantly attenuated even in the presence of IL-6, the putative activator of the JAK/STAT pathway. Conclusion: FMSP can effectively target BCSCs via ROS production and modulation of major signaling pathways that contribute to the stemness of breast cancer cells, and therefore, might be considered a promising anticancer agent after in vivo studies.

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Biomechanical and Biophysical Properties of Breast Cancer Cells Under Varying Glycemic Regimens

Breast Cancer Basic and Clinical Research ◽

10.1177/1178223420972362 ◽

2020 ◽

Vol 14 ◽

pp. 117822342097236

Author(s):

Diganta Dutta ◽

Xavier-Lewis Palmer ◽

Jose Ortega-Rodas ◽

Vasundhara Balraj ◽

Indrani Ghosh Dastider ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Young’S Modulus ◽

High Glucose ◽

Breast Cancer Cells ◽

Mammary Epithelial Cells ◽

Young's Modulus ◽

Malignant Cells ◽

Biophysical Properties ◽

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Diabetes accelerates cancer cell proliferation and metastasis, particularly for cancers of the pancreas, liver, breast, colon, and skin. While pathways linking the 2 disease conditions have been explored extensively, there is a lack of information on whether there could be cytoarchitectural changes induced by glucose which predispose cancer cells to aggressive phenotypes. It was thus hypothesized that exposure to diabetes/high glucose alters the biomechanical and biophysical properties of cancer cells more than the normal cells, which aids in advancing the cancer. For this study, atomic force microscopy indentation was used through microscale probing of multiple human breast cancer cells (MCF-7, MDA-MB-231), and human normal mammary epithelial cells (MCF-10A), under different levels of glycemic stress. These were used to study both benign and malignant breast tissue behaviors. Benign cells (MCF-10A) recorded higher Young’s modulus values than malignant cells (MCF-7 and MDA-231) under normoglycemic conditions, which agrees with the current literature. Moreover, exposure to high glucose (for 48 hours) decreased Young’s modulus in both benign and malignant cells, to the effect that the cancer cells showed a complete loss in elasticity with high glucose. This provides a possible insight into a link between glycemic stress and cytoskeletal strength. This work suggests that reducing glycemic stress in cancer patients and those at risk can prove beneficial in restoring normal cytoskeletal structure.

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