The Experts below are selected from a list of 168 Experts worldwide ranked by ideXlab platform
Rita Nahta - One of the best experts on this subject based on the ideXlab platform.
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Delphinidin Inhibits HER2 and Erk1/2 Signaling and Suppresses Growth of HER2-Overexpressing and Triple Negative Breast Cancer Cell Lines
Breast cancer : basic and clinical research, 2011Co-Authors: Tuba Ozbay, Rita NahtaAbstract:Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables. Delphinidin is also the major bioactive component found in many dietary supplements that are currently consumed as complementary cancer medicine including pomegranate extract. The purpose of the current study was to determine the in vitro biological effects of delphinidin on established breast cancer cell lines of varying molecular subtypes in comparison to non-transformed breast epithelial cells. We examined cell proliferation, apoptosis, and growth inhibition in response to delphinidin using a tetrazolium salt-based assay, DNA fragmentation assay, and anchorage-independent growth assay. In comparison to vehicle control, delphinidin inhibited proliferation (P < 0.05), blocked anchorage-independent growth (P < 0.05), and induced apoptosis (P < 0.05) of ER-positive, triple negative, and HER2-overexpressing breast cancer cell lines with limited toxicity to non-transformed breast epithelial cells. MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin. In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling. Since delphinidin is often consumed as a complementary cancer medicine, the effect of delphinidin on response to specific HER2-targeted breast cancer therapies was examined by proliferation assay. Results of these Drug combination studies suggested potential Antagonism between delphinidin and HER2-directed treatments. In summary, the data presented here suggest that single agent delphinidin exhibits growth inhibitory activity in breast cancer cells of various molecular subtypes, but raise concerns regarding potential Drug Antagonism when used in combination with existing targeted therapies in HER2-overexpressing breast cancer.
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delphinidin inhibits her2 and erk1 2 signaling and suppresses growth of her2 overexpressing and triple negative breast cancer cell lines
Breast Cancer: Basic and Clinical Research, 2011Co-Authors: Tuba Ozbay, Rita NahtaAbstract:Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables. Delphinidin is also the major bioactive component found in many dietary supplements that are currently consumed as complementary cancer medicine including pomegranate extract. The purpose of the current study was to determine the in vitro biological effects of delphinidin on established breast cancer cell lines of varying molecular subtypes in comparison to non-transformed breast epithelial cells. We examined cell proliferation, apoptosis, and growth inhibition in response to delphinidin using a tetrazolium salt-based assay, DNA fragmentation assay, and anchorage-independent growth assay. In comparison to vehicle control, delphinidin inhibited proliferation (P < 0.05), blocked anchorage-independent growth (P < 0.05), and induced apoptosis (P < 0.05) of ER-positive, triple negative, and HER2-overexpressing breast cancer cell lines with limited toxicity to non-transformed breast epithelial cells. MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin. In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling. Since delphinidin is often consumed as a complementary cancer medicine, the effect of delphinidin on response to specific HER2-targeted breast cancer therapies was examined by proliferation assay. Results of these Drug combination studies suggested potential Antagonism between delphinidin and HER2-directed treatments. In summary, the data presented here suggest that single agent delphinidin exhibits growth inhibitory activity in breast cancer cells of various molecular subtypes, but raise concerns regarding potential Drug Antagonism when used in combination with existing targeted therapies in HER2-overexpressing breast cancer.
Tuba Ozbay - One of the best experts on this subject based on the ideXlab platform.
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Delphinidin Inhibits HER2 and Erk1/2 Signaling and Suppresses Growth of HER2-Overexpressing and Triple Negative Breast Cancer Cell Lines
Breast cancer : basic and clinical research, 2011Co-Authors: Tuba Ozbay, Rita NahtaAbstract:Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables. Delphinidin is also the major bioactive component found in many dietary supplements that are currently consumed as complementary cancer medicine including pomegranate extract. The purpose of the current study was to determine the in vitro biological effects of delphinidin on established breast cancer cell lines of varying molecular subtypes in comparison to non-transformed breast epithelial cells. We examined cell proliferation, apoptosis, and growth inhibition in response to delphinidin using a tetrazolium salt-based assay, DNA fragmentation assay, and anchorage-independent growth assay. In comparison to vehicle control, delphinidin inhibited proliferation (P < 0.05), blocked anchorage-independent growth (P < 0.05), and induced apoptosis (P < 0.05) of ER-positive, triple negative, and HER2-overexpressing breast cancer cell lines with limited toxicity to non-transformed breast epithelial cells. MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin. In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling. Since delphinidin is often consumed as a complementary cancer medicine, the effect of delphinidin on response to specific HER2-targeted breast cancer therapies was examined by proliferation assay. Results of these Drug combination studies suggested potential Antagonism between delphinidin and HER2-directed treatments. In summary, the data presented here suggest that single agent delphinidin exhibits growth inhibitory activity in breast cancer cells of various molecular subtypes, but raise concerns regarding potential Drug Antagonism when used in combination with existing targeted therapies in HER2-overexpressing breast cancer.
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delphinidin inhibits her2 and erk1 2 signaling and suppresses growth of her2 overexpressing and triple negative breast cancer cell lines
Breast Cancer: Basic and Clinical Research, 2011Co-Authors: Tuba Ozbay, Rita NahtaAbstract:Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables. Delphinidin is also the major bioactive component found in many dietary supplements that are currently consumed as complementary cancer medicine including pomegranate extract. The purpose of the current study was to determine the in vitro biological effects of delphinidin on established breast cancer cell lines of varying molecular subtypes in comparison to non-transformed breast epithelial cells. We examined cell proliferation, apoptosis, and growth inhibition in response to delphinidin using a tetrazolium salt-based assay, DNA fragmentation assay, and anchorage-independent growth assay. In comparison to vehicle control, delphinidin inhibited proliferation (P < 0.05), blocked anchorage-independent growth (P < 0.05), and induced apoptosis (P < 0.05) of ER-positive, triple negative, and HER2-overexpressing breast cancer cell lines with limited toxicity to non-transformed breast epithelial cells. MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin. In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling. Since delphinidin is often consumed as a complementary cancer medicine, the effect of delphinidin on response to specific HER2-targeted breast cancer therapies was examined by proliferation assay. Results of these Drug combination studies suggested potential Antagonism between delphinidin and HER2-directed treatments. In summary, the data presented here suggest that single agent delphinidin exhibits growth inhibitory activity in breast cancer cells of various molecular subtypes, but raise concerns regarding potential Drug Antagonism when used in combination with existing targeted therapies in HER2-overexpressing breast cancer.
Terry P Kenakin - One of the best experts on this subject based on the ideXlab platform.
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Chapter 4 – Drug Antagonism: Orthosteric Drug Effects
Pharmacology in Drug Discovery and Development, 2017Co-Authors: Terry P KenakinAbstract:This chapter deals with the quantification of the effects of antagonists to yield empirical measures of antagonist potency. Beginning with the premise that there are two possible modes of action of Antagonism; orthosteric blockade (occlusion of the agonist binding site) and allosteric modulation, this chapter focuses on orthosteric Antagonism. Estimates of antagonist potency can be obtained for all modes of Antagonism through a pA2 value and/or a pIC50 of Antagonism of a fixed agonist effect. Patterns of Antagonism are then discussed from the standpoint of using these to identify the mechanism of antagonist action (eg, orthosteric antagonists producing steric hindrance of agonists). The chapter then discusses how these mechanisms can be used to identify the appropriate mathematical analysis to yield estimates of true system-independent antagonist potency that transcend cell type and measuring system.
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chapter 4 Drug Antagonism orthosteric Drug effects
Pharmacology in Drug Discovery and Development (Second Edition)#R##N#Understanding Drug Response, 2017Co-Authors: Terry P KenakinAbstract:This chapter deals with the quantification of the effects of antagonists to yield empirical measures of antagonist potency. Beginning with the premise that there are two possible modes of action of Antagonism; orthosteric blockade (occlusion of the agonist binding site) and allosteric modulation, this chapter focuses on orthosteric Antagonism. Estimates of antagonist potency can be obtained for all modes of Antagonism through a pA2 value and/or a pIC50 of Antagonism of a fixed agonist effect. Patterns of Antagonism are then discussed from the standpoint of using these to identify the mechanism of antagonist action (eg, orthosteric antagonists producing steric hindrance of agonists). The chapter then discusses how these mechanisms can be used to identify the appropriate mathematical analysis to yield estimates of true system-independent antagonist potency that transcend cell type and measuring system.
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Chapter 6 – Orthosteric Drug Antagonism
A Pharmacology Primer, 2014Co-Authors: Terry P KenakinAbstract:This chapter discusses how the real time relative kinetics of agonist and antagonist offset from the receptor determines whether or not orthosteric antagonists produce competitive, a hemi-equilibrium state or non-competitive Antagonism. These kinetics effects also are discussed in terms of the target coverage produced in vivo. In addition to these mechanisms, chemical Antagonism (interaction between ligands) and irreversible Antagonism are considered.
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chapter 6 orthosteric Drug Antagonism
A Pharmacology Primer (Fourth Edition)#R##N#Techniques for More Effective and Strategic Drug Discovery, 2014Co-Authors: Terry P KenakinAbstract:This chapter discusses how the real time relative kinetics of agonist and antagonist offset from the receptor determines whether or not orthosteric antagonists produce competitive, a hemi-equilibrium state or non-competitive Antagonism. These kinetics effects also are discussed in terms of the target coverage produced in vivo. In addition to these mechanisms, chemical Antagonism (interaction between ligands) and irreversible Antagonism are considered.
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Drug Antagonism: Orthosteric Drug Effects
Pharmacology in Drug Discovery, 2012Co-Authors: Terry P KenakinAbstract:Publisher Summary In this chapter, readers should be able to quantify the effects of antagonists to yield empirical measures of antagonist potency. They will also be able to relate patterns of Antagonism produced by orthosteric antagonists to mechanisms of antagonist action. These mechanisms can be used to apply the appropriate mathematical analysis to yield estimates of true system-independent antagonist potency that transcend cell type and measuring system. This chapter deals with molecules that bind to the target without themselves causing a change, but do interfere with agonists producing response; this is the process of Antagonism. The main reason for noting the patterns of Antagonism produced by orthosteric antagonists with various rates of offset kinetics is to determine the correct method of estimating antagonist potency. In practical terms, all that is required to estimate the potency of a simple competitive antagonist is the determination of the effect of a single concentration of the antagonist on an agonist dose-response curve. The in-vivo effects of various antagonists and schematic diagrams depicting the logic used to determine the mode of action and potency of an antagonist is explained.
Michael J. Lee - One of the best experts on this subject based on the ideXlab platform.
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Drug Antagonism and single-agent dominance result from differences in death kinetics
Nature chemical biology, 2020Co-Authors: Ryan Richards, Hannah R. Schwartz, Megan E. Honeywell, Mariah S. Stewart, Peter Cruz-gordillo, Anna J. Joyce, Benjamin D. Landry, Michael J. LeeAbstract:Cancer treatment generally involves Drugs used in combinations. Most previous work has focused on identifying and understanding synergistic Drug–Drug interactions; however, understanding antagonistic interactions remains an important and understudied issue. To enrich for Antagonism and reveal common features of these combinations, we screened all pairwise combinations of Drugs characterized as activators of regulated cell death. This network is strongly enriched for Antagonism, particularly a form of Antagonism that we call ‘single-agent dominance’. Single-agent dominance refers to Antagonisms in which a two-Drug combination phenocopies one of the two agents. Dominance results from differences in cell death onset time, with dominant Drugs acting earlier than their suppressed counterparts. We explored mechanisms by which parthanatotic agents dominate apoptotic agents, finding that dominance in this scenario is caused by mutually exclusive and conflicting use of Poly(ADP-ribose) polymerase 1 (PARP1). Taken together, our study reveals death kinetics as a predictive feature of Antagonism, due to inhibitory crosstalk between cell death pathways. Drug combinations consisting of two cell death-targeting Drugs are enriched for Antagonism and ‘single-agent dominance’, where the faster-acting Drug suppresses the slower-acting Drug due to inhibitory crosstalk between cell death pathways.
Uwe Wagner - One of the best experts on this subject based on the ideXlab platform.
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Effects of Celecoxib and Ly117018 Combination on Human Breast Cancer Cells in Vitro
Breast cancer : basic and clinical research, 2009Co-Authors: Klaus H. Baumann, Elmar Klusmeier, Isabel Eggemann, Silke Reinartz, Achim Almeroth, Mathias Kalder, Uwe WagnerAbstract:Activation and signalling of estrogen receptor (ER) and COX-2 represent two important pathways in breast cancer cell regulation. Activation of either pathway is associated with breast cancer cell proliferation and eventually malignant progression. Raloxifene analogue, Ly117018, a selective estrogen receptor modulator and celecoxib, a specific COX- 2 inhibitor have been shown to inhibit breast cancer cell proliferation when used alone in vitro and in vivo. In this study, the combined Drug effects on hormone-dependent MCF-7 and hormone-independent MDA-MB-435 cells in vitro were evaluated. Cell proliferation assays excluded Drug Antagonism and revealed a moderate synergistic growth inhibitory activity of Ly117018 and celecoxib on both cell lines when combined in specific concentrations. Growth inhibition of either compound was not associated with cell cycle arrest. In MCF-7 cells, western blot analysis revealed a decreased phosphorylation of the AKT protein by either agent alone or in combination. In MDA-MB-435 cells, celecoxib alone induced an increase in AKT phosphorylation relative to total AKT protein; this effect was decreased in the presence of Ly117018. These results indicate that these two Drugs are non-antagonistic; and when combined in specific concentrations, moderate synergistic antiproliferative activity of celecoxib and Ly117018 were observed in hormone-dependent MCF-7 and hormone- independent MDA-MB-435 cells associated with changes in cell cycle distribution and regulation of AKT protein and phosphorylation. These findings further support a central role of the ER- and COX-2 pathways in human breast cancer cells.
