Munevver Baran, Gozde Ozge Onder, Ozge Goktepe, Arzu Yay
Obstacles to the successful treatment of breast cancer patients with chemotherapeutic agents can be overcome with effective new strategies. It is still unclear how folic acid affects the onset and spread of breast cancer. The purpose of this study was to determine how folic acid affected the apoptotic and autophagic pathways of the breast cancer cell lines MCF-7 and MDA-MB-231. In the present study, folic acid was applied to MCF-7 and MDA-MB-231 breast cancer cell lines at different concentrations and for different durations. MTT analysis was used to investigate cytotoxic activity. All groups underwent the Tunel staining procedure to identify apoptosis and the immunofluorescence staining approach to identify the autophagic pathway. 24-hour folic acid values were accepted as the most appropriate cytotoxic dose. In MCF-7, cell cycle arrest was observed in the S phase and MDA-MB-231 G1/G0 phases. When apoptotic TUNEL staining was evaluated in both cell lines, folic acid significantly increased apoptosis. While a significant difference was observed between the groups in terms of Beclin 1 immunoreactivity in the MDA-MB-231 cell line, there was no significant difference in the MCF-7 cell line. In addition, statistical significance was not observed LC3 immunoreactivity in both cell lines. In the study, it was observed that folic acid induced autophagy at the initial stage in the MDA-MB-231 cell line but had no inductive effect in the MCF-7 cell line. In conclusion, our findings showed that folic acid has a potential cytotoxic and therapeutic effect on MCF-7 and MDA-MB-231 breast cancer cell lines.
{"title":"Role of apoptosis and autophagy in folic acid-induced cytotoxicity of human breast cancer cells in vitro","authors":"Munevver Baran, Gozde Ozge Onder, Ozge Goktepe, Arzu Yay","doi":"10.1111/fcp.12948","DOIUrl":"10.1111/fcp.12948","url":null,"abstract":"<p>Obstacles to the successful treatment of breast cancer patients with chemotherapeutic agents can be overcome with effective new strategies. It is still unclear how folic acid affects the onset and spread of breast cancer. The purpose of this study was to determine how folic acid affected the apoptotic and autophagic pathways of the breast cancer cell lines MCF-7 and MDA-MB-231. In the present study, folic acid was applied to MCF-7 and MDA-MB-231 breast cancer cell lines at different concentrations and for different durations. MTT analysis was used to investigate cytotoxic activity. All groups underwent the Tunel staining procedure to identify apoptosis and the immunofluorescence staining approach to identify the autophagic pathway. 24-hour folic acid values were accepted as the most appropriate cytotoxic dose. In MCF-7, cell cycle arrest was observed in the S phase and MDA-MB-231 G1/G0 phases. When apoptotic TUNEL staining was evaluated in both cell lines, folic acid significantly increased apoptosis. While a significant difference was observed between the groups in terms of Beclin 1 immunoreactivity in the MDA-MB-231 cell line, there was no significant difference in the MCF-7 cell line. In addition, statistical significance was not observed LC3 immunoreactivity in both cell lines. In the study, it was observed that folic acid induced autophagy at the initial stage in the MDA-MB-231 cell line but had no inductive effect in the MCF-7 cell line. In conclusion, our findings showed that folic acid has a potential cytotoxic and therapeutic effect on MCF-7 and MDA-MB-231 breast cancer cell lines.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10069986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cannabis, more commonly known as marijuana or hemp, has been used for centuries to treat various conditions. Cannabis contains two main components cannabidiol (CBD) and tetrahydrocannabinol (THC). CBD, unlike THC, is devoid of psychoactive effects and is well tolerated by the human body but has no direct effect on the receptors of the endocannabid system, despite the lack of action on the receptors of the endocannabid system.
Objectives and methods
We have prepared a literature review based on the latest available literature regarding the analgesic effects of CBD. CBD has a wide range of effects on the human body. In this study, we will present the potential mechanisms responsible for the analgesic effect of CBD. To the best of our knowledge, this is the first review to explore the analgesic mechanisms of CBD.
Results and conclusion
The analgesic effect of CBD is complex and still being researched. CBD models the perception of pain by acting on G protein-coupled receptors. Another group of receptors that CBD acts on are serotonergic receptors. The effect of CBD on an enzyme of potential importance in the production of inflammatory factors such as cyclooxygenases and lipoxygenases has also been confirmed. The presented potential mechanisms of CBD's analgesic effect are currently being extensively studied.
{"title":"Can cannabidiol have an analgesic effect?","authors":"Bartłomiej Kulesza, Marek Mazurek, Jacek Kurzepa","doi":"10.1111/fcp.12947","DOIUrl":"10.1111/fcp.12947","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cannabis, more commonly known as marijuana or hemp, has been used for centuries to treat various conditions. Cannabis contains two main components cannabidiol (CBD) and tetrahydrocannabinol (THC). CBD, unlike THC, is devoid of psychoactive effects and is well tolerated by the human body but has no direct effect on the receptors of the endocannabid system, despite the lack of action on the receptors of the endocannabid system.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives and methods</h3>\u0000 \u0000 <p>We have prepared a literature review based on the latest available literature regarding the analgesic effects of CBD. CBD has a wide range of effects on the human body. In this study, we will present the potential mechanisms responsible for the analgesic effect of CBD. To the best of our knowledge, this is the first review to explore the analgesic mechanisms of CBD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results and conclusion</h3>\u0000 \u0000 <p>The analgesic effect of CBD is complex and still being researched. CBD models the perception of pain by acting on G protein-coupled receptors. Another group of receptors that CBD acts on are serotonergic receptors. The effect of CBD on an enzyme of potential importance in the production of inflammatory factors such as cyclooxygenases and lipoxygenases has also been confirmed. The presented potential mechanisms of CBD's analgesic effect are currently being extensively studied.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10004065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bruno Matheus Facchin, Tainá Larissa Lubschinski, Yeo Jim Kinoshita Moon, Paula Giarola Fragoso de Oliveira, Bianca Klafke Beck, Ziliani da Silva Buss, Luiz Antonio Escorteganha Pollo, Maique Weber Biavatti, Louis Pergaud Sandjo, Eduardo Monguilhott Dalmarco
Introduction
Inflammation is a physiological event that protects the organism against different factors that lead to loss of tissue homeostasis. Dihydropyridine (DHP) derivatives are heterocyclic compounds known for their different biological activities, including anti-inflammatory activities.
Objective
To evaluate the anti-inflammatory activity of 1,4-dihydropyridine (1,4-DHP) derivatives using anti-inflammatory models in vitro, in RAW264.7 cells induced by lipopolysaccharide (LPS) and in vivo using the acute lung injury (ALI) model in mice.
Results
Fifteen compounds derived from 1,4-DHP were tested in RAW264.7 cells for their cytotoxic effect and cell viability. Thereafter, only the six compounds that showed the highest cell viability were tested for the production or inhibition of the pro-inflammatory cytokine interleukin 6 (IL-6). The best compound (compound 4) was tested for its anti-inflammatory effects in vitro and in vivo, showing inhibition of nitric oxide (NO), pro-inflammatory cytokines, increased phagocytic activity, and an increase in IL-10 in vitro. In in vivo tests, compound 4 also reduces the levels of NO, myeloperoxidase (MPO) activity, leukocyte migration, and exudation, as well as reducing the levels of tumor necrosis factor-alpha (TNF-α) and IL-6 and preventing the loss in the lung architecture.
Conclusion
This compound showed important anti-inflammatory activity, with a significant ability to reduce the production of pro-inflammatory mediators and increase the phagocytic activity of macrophages and anti-inflammatory mediator secretion (IL-10). These findings led us to hypothesize that this compound can repolarize the macrophage response to an anti-inflammatory profile (M2). Moreover, it was also able to maintain its anti-inflammatory activity in vivo experiments.
{"title":"Evaluation of the anti-inflammatory effect of 1,4-dihydropyridine derivatives","authors":"Bruno Matheus Facchin, Tainá Larissa Lubschinski, Yeo Jim Kinoshita Moon, Paula Giarola Fragoso de Oliveira, Bianca Klafke Beck, Ziliani da Silva Buss, Luiz Antonio Escorteganha Pollo, Maique Weber Biavatti, Louis Pergaud Sandjo, Eduardo Monguilhott Dalmarco","doi":"10.1111/fcp.12945","DOIUrl":"10.1111/fcp.12945","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Inflammation is a physiological event that protects the organism against different factors that lead to loss of tissue homeostasis. Dihydropyridine (DHP) derivatives are heterocyclic compounds known for their different biological activities, including anti-inflammatory activities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To evaluate the anti-inflammatory activity of 1,4-dihydropyridine (1,4-DHP) derivatives using anti-inflammatory models in vitro, in RAW264.7 cells induced by lipopolysaccharide (LPS) and in vivo using the acute lung injury (ALI) model in mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Fifteen compounds derived from 1,4-DHP were tested in RAW264.7 cells for their cytotoxic effect and cell viability. Thereafter, only the six compounds that showed the highest cell viability were tested for the production or inhibition of the pro-inflammatory cytokine interleukin 6 (IL-6). The best compound (compound 4) was tested for its anti-inflammatory effects in vitro and in vivo, showing inhibition of nitric oxide (NO), pro-inflammatory cytokines, increased phagocytic activity, and an increase in IL-10 in vitro. In in vivo tests, compound 4 also reduces the levels of NO, myeloperoxidase (MPO) activity, leukocyte migration, and exudation, as well as reducing the levels of tumor necrosis factor-alpha (TNF-α) and IL-6 and preventing the loss in the lung architecture.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This compound showed important anti-inflammatory activity, with a significant ability to reduce the production of pro-inflammatory mediators and increase the phagocytic activity of macrophages and anti-inflammatory mediator secretion (IL-10). These findings led us to hypothesize that this compound can repolarize the macrophage response to an anti-inflammatory profile (M2). Moreover, it was also able to maintain its anti-inflammatory activity in vivo experiments.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9957375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Larissa da Silva, Isydório Alves Donato, Suieny Rodrigues Bezerra, Hélcio Silva dos Santos, Paulo Nogueira Bandeira, Maria Thalia Ramos do Nascimento, Jesyka Macêdo Guedes, Priscila Ramos Freitas, Ana Carolina Justino de Araújo, Thiago Sampaio de Freitas, Henrique Douglas Melo Coutinho, Yedda Maria Lobo Soares de Matos, Lígia Cláudia Castro de Oliveira, Francisco Assis Bezerra da Cunha
Background
The bacterium Staphylococcus aureus has stood out for presenting a high adaptability, acquiring resistance to multiple drugs. The search for natural or synthetic compounds with antibacterial properties capable of reversing the resistance of S. aureus is the main challenge to be overcome today. Natural products such as chalcones are substances present in the secondary metabolism of plants, presenting important biological activities such as antitumor, antidiabetic, and antimicrobial activity.
Objectives
In this context, the aim of this work was to synthesize the chalcone (2E)-1-(3'-aminophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-one with nomenclature CMADMA, confirm its structure by nuclear magnetic resonance (NMR), and evaluate its antibacterial properties.
Methods
The synthesis methodology used was that of Claisen-Schmidt, and spectroscopic characterization was performed by NMR. For microbiological assays, the broth microdilution methodology was adopted in order to analyze the antibacterial potential of chalcones and to analyze their ability to act as a possible inhibitor of β-lactamase and efflux pump resistance mechanisms, present in S. aureus strain K4100.
Results
The results obtained show that CMADMA does not show direct antibacterial activity, expressing a MIC of ≥1024 μg/mL, or on the enzymatic mechanism of β-lactamase; however, when associated with ethidium bromide in efflux pump inhibition assays, CMADMA showed promising activity by reducing the MIC of the bromide from 64 to 32 μg/mL.
Conclusion
We conclude that the chalcone synthesized in this study is a promising substance to combat bacterial resistance, possibly acting in the inhibition of the QacC efflux pump present in S. aureus strain K4100, as evidenced by the reduction in the MIC of ethidium bromide.
背景：金黄色葡萄球菌具有很强的适应性，可对多种药物产生抗药性。寻找能逆转金黄色葡萄球菌抗药性的天然或合成抗菌化合物是当今面临的主要挑战。天然产物（如查尔酮）是存在于植物二次代谢中的物质，具有重要的生物活性，如抗肿瘤、抗糖尿病和抗菌活性：在此背景下，本研究旨在合成(2E)-1-(3'-氨基苯基)-3-(4-二甲基氨基苯基)-丙-2-烯-1-酮（命名为 CMADMA），通过核磁共振（NMR）确认其结构，并评估其抗菌特性：方法：采用克莱森-施密特合成方法，并通过核磁共振进行光谱鉴定。在微生物检测方面，采用肉汤微稀释法分析查耳酮的抗菌潜力，并分析其作为金黄色葡萄球菌菌株 K4100 中存在的β-内酰胺酶和外排泵耐药机制的可能抑制剂的能力：结果表明，CMADMA 没有显示出直接的抗菌活性，其 MIC ≥1024 μg/mL，也没有对 β-内酰胺酶的酶学机制产生影响；然而，当与溴化乙锭一起进行外排泵抑制试验时，CMADMA 显示出了良好的活性，将溴化乙锭的 MIC 从 64 μg/mL降至 32 μg/mL：我们得出的结论是，本研究中合成的查尔酮是一种很有希望消除细菌耐药性的物质，其作用可能是抑制金黄色葡萄球菌菌株 K4100 中的 QacC 外排泵，溴化乙锭的 MIC 值降低就证明了这一点。
{"title":"Synthesis, spectroscopic characterization, and antibacterial activity of chalcone (2E)-1-(3′-aminophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-one against multiresistant Staphylococcus aureus carrier of efflux pump mechanisms and β-lactamase","authors":"Larissa da Silva, Isydório Alves Donato, Suieny Rodrigues Bezerra, Hélcio Silva dos Santos, Paulo Nogueira Bandeira, Maria Thalia Ramos do Nascimento, Jesyka Macêdo Guedes, Priscila Ramos Freitas, Ana Carolina Justino de Araújo, Thiago Sampaio de Freitas, Henrique Douglas Melo Coutinho, Yedda Maria Lobo Soares de Matos, Lígia Cláudia Castro de Oliveira, Francisco Assis Bezerra da Cunha","doi":"10.1111/fcp.12938","DOIUrl":"10.1111/fcp.12938","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The bacterium <i>Staphylococcus</i> aureus has stood out for presenting a high adaptability, acquiring resistance to multiple drugs. The search for natural or synthetic compounds with antibacterial properties capable of reversing the resistance of <i>S. aureus</i> is the main challenge to be overcome today. Natural products such as chalcones are substances present in the secondary metabolism of plants, presenting important biological activities such as antitumor, antidiabetic, and antimicrobial activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>In this context, the aim of this work was to synthesize the chalcone (2<i>E</i>)-1-(3'-aminophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-one with nomenclature CMADMA, confirm its structure by nuclear magnetic resonance (NMR), and evaluate its antibacterial properties.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The synthesis methodology used was that of Claisen-Schmidt, and spectroscopic characterization was performed by NMR. For microbiological assays, the broth microdilution methodology was adopted in order to analyze the antibacterial potential of chalcones and to analyze their ability to act as a possible inhibitor of β-lactamase and efflux pump resistance mechanisms, present in S. aureus strain K4100.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results obtained show that CMADMA does not show direct antibacterial activity, expressing a MIC of ≥1024 μg/mL, or on the enzymatic mechanism of β-lactamase; however, when associated with ethidium bromide in efflux pump inhibition assays, CMADMA showed promising activity by reducing the MIC of the bromide from 64 to 32 μg/mL.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We conclude that the chalcone synthesized in this study is a promising substance to combat bacterial resistance, possibly acting in the inhibition of the QacC efflux pump present in <i>S. aureus</i> strain K4100, as evidenced by the reduction in the MIC of ethidium bromide.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10235164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qi Rao, He Yu, Ruochan Li, Bin He, Yuxue Wang, Xiaohong Guo, Gang Zhao, Fenghua Wu
Background
Dihydroartemisinin (DHA) is an artemisinin derivative known for its antimalarial properties. It has also shown potential as an anti-tumor and anti-angiogenic agent. However, its specific role in inhibiting angiogenesis in breast cancer is not well understood.
Objectives
We aimed to investigate the anti-angiogenesis effect of DHA on breast cancer and explore its potential as a therapeutic drug. Our objectives were to assess the impact of DHA on neovascularization induced by MDA-MB-231 cells, evaluate its effects on vessel sprout and tube-formation in vascular endothelial cells, and analyze the expression of key angiogenesis-related proteins.
Methods
Using a chicken chorioallantoic membrane (CAM) model, we cultured MDA-MB-231 cells and treated them with DHA. We assessed neovascularization and cultured vascular endothelial cells with DHA-treated cell media to evaluate vessel sprout and tube-formation. Protein expression levels of VEGF, MMP-2, and MMP-9 were analyzed using Western blotting.
Results
DHA significantly attenuated neovascularization induced by MDA-MB-231 cells. It also suppressed vessel sprout and tube-formation of HUVEC cells when exposed to DHA-treated cell media. Furthermore, DHA downregulated the expression of VEGF, MMP-2, and MMP-9 proteins. Mechanistically, DHA inhibited the phosphorylation of PI3K, AKT, ERK, and NF-κB proteins in tumor cells.
Conclusions
Our study provides evidence of the inhibitory effect of DHA on breast cancer angiogenesis. These findings support the potential of DHA as an anti-breast cancer drug and warrant further investigation for its therapeutic applications.
背景：双氢青蒿素（DHA）是一种青蒿素衍生物，因其抗疟特性而闻名。它还具有抗肿瘤和抗血管生成的潜力。然而，它在抑制乳腺癌血管生成方面的具体作用尚不十分清楚：我们旨在研究 DHA 对乳腺癌的抗血管生成作用，并探索其作为治疗药物的潜力。我们的目标是评估 DHA 对 MDA-MB-231 细胞诱导的新生血管生成的影响，评估其对血管内皮细胞的血管萌发和管形成的影响，并分析关键血管生成相关蛋白的表达：方法：我们使用鸡绒毛膜（CAM）模型培养 MDA-MB-231 细胞并用 DHA 处理。我们评估了血管新生情况，并用 DHA 处理过的细胞培养基培养血管内皮细胞，以评估血管萌芽和管形成情况。用 Western 印迹法分析了血管内皮生长因子、MMP-2 和 MMP-9 的蛋白表达水平：结果：DHA能明显减轻MDA-MB-231细胞诱导的新生血管形成。它还抑制了暴露于经 DHA 处理的细胞介质中的 HUVEC 细胞的血管萌发和管形成。此外，DHA 还能降低血管内皮生长因子、MMP-2 和 MMP-9 蛋白的表达。从机理上讲，DHA抑制了肿瘤细胞中PI3K、AKT、ERK和NF-κB蛋白的磷酸化：我们的研究提供了 DHA 对乳腺癌血管生成有抑制作用的证据。这些发现支持了 DHA 作为抗乳腺癌药物的潜力，值得进一步研究其治疗应用。
{"title":"Dihydroartemisinin inhibits angiogenesis in breast cancer via regulating VEGF and MMP-2/-9","authors":"Qi Rao, He Yu, Ruochan Li, Bin He, Yuxue Wang, Xiaohong Guo, Gang Zhao, Fenghua Wu","doi":"10.1111/fcp.12941","DOIUrl":"10.1111/fcp.12941","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Dihydroartemisinin (DHA) is an artemisinin derivative known for its antimalarial properties. It has also shown potential as an anti-tumor and anti-angiogenic agent. However, its specific role in inhibiting angiogenesis in breast cancer is not well understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We aimed to investigate the anti-angiogenesis effect of DHA on breast cancer and explore its potential as a therapeutic drug. Our objectives were to assess the impact of DHA on neovascularization induced by MDA-MB-231 cells, evaluate its effects on vessel sprout and tube-formation in vascular endothelial cells, and analyze the expression of key angiogenesis-related proteins.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using a chicken chorioallantoic membrane (CAM) model, we cultured MDA-MB-231 cells and treated them with DHA. We assessed neovascularization and cultured vascular endothelial cells with DHA-treated cell media to evaluate vessel sprout and tube-formation. Protein expression levels of VEGF, MMP-2, and MMP-9 were analyzed using Western blotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>DHA significantly attenuated neovascularization induced by MDA-MB-231 cells. It also suppressed vessel sprout and tube-formation of HUVEC cells when exposed to DHA-treated cell media. Furthermore, DHA downregulated the expression of VEGF, MMP-2, and MMP-9 proteins. Mechanistically, DHA inhibited the phosphorylation of PI3K, AKT, ERK, and NF-κB proteins in tumor cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study provides evidence of the inhibitory effect of DHA on breast cancer angiogenesis. These findings support the potential of DHA as an anti-breast cancer drug and warrant further investigation for its therapeutic applications.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9870113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paula Montero, Celia Sanz, Jose Alejandro Pérez-Fidalgo, Martín Pérez-Leal, Javier Milara, Julio Cortijo
Background
Paclitaxel (PTX) is a microtubule-stabilizing antineoplastic that has been shown to damage healthy tissues like the skin. Hyperpigmentation can be found among the adverse effects caused by PTX, but the literature is limited and the mechanisms driving PTX-induced pigmentary alterations are unknown.
Objectives
This study aimed to describe the pigmentary alterations caused by PTX and to determine the effects of PTX on melanocytes.
Methods
Pigmentary skin alterations were measured in 20 gynecological cancer patients under PTX treatment by using specific probes, which determine the melanin index and the pigmentation level. Melanocytes were incubated with paclitaxel to analyze melanogenesis markers gene expression, melanin content, and transcription factors activation.
Results
Paclitaxel induced alterations in the skin pigmentation with no visible clinical manifestations. Gynecological cancer patients under paclitaxel treatment had an increase in the melanin index and pigmentation levels. In vitro, PTX exposure to melanocytes increased the expression of melanogenesis markers, melanin content, and induced activation of ERK and MITF.
Conclusions
The results suggest that PTX alters pigmentation in patients with no clinically visible manifestations, and these alterations might be driven by its capacity to stimulate melanogenesis on melanocytes through the MITF activation pathway.
{"title":"Paclitaxel alters melanogenesis and causes pigmentation in the skin of gynecological cancer patients","authors":"Paula Montero, Celia Sanz, Jose Alejandro Pérez-Fidalgo, Martín Pérez-Leal, Javier Milara, Julio Cortijo","doi":"10.1111/fcp.12943","DOIUrl":"10.1111/fcp.12943","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Paclitaxel (PTX) is a microtubule-stabilizing antineoplastic that has been shown to damage healthy tissues like the skin. Hyperpigmentation can be found among the adverse effects caused by PTX, but the literature is limited and the mechanisms driving PTX-induced pigmentary alterations are unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study aimed to describe the pigmentary alterations caused by PTX and to determine the effects of PTX on melanocytes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Pigmentary skin alterations were measured in 20 gynecological cancer patients under PTX treatment by using specific probes, which determine the melanin index and the pigmentation level. Melanocytes were incubated with paclitaxel to analyze melanogenesis markers gene expression, melanin content, and transcription factors activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Paclitaxel induced alterations in the skin pigmentation with no visible clinical manifestations. Gynecological cancer patients under paclitaxel treatment had an increase in the melanin index and pigmentation levels. In vitro, PTX exposure to melanocytes increased the expression of melanogenesis markers, melanin content, and induced activation of ERK and MITF.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The results suggest that PTX alters pigmentation in patients with no clinically visible manifestations, and these alterations might be driven by its capacity to stimulate melanogenesis on melanocytes through the MITF activation pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.12943","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9912671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna Seetsi, David D. N'da, Nthatisi Molefe-Nyembe, Keisuke Suganuma, Tsepo Ramatla, Oriel Thekisoe
Human African trypanosomosis (HAT) which is also known as sleeping sickness is caused by Trypanosoma brucei gambiense that is endemic in western and central Africa and T. b. rhodesiense that is endemic in eastern and southern Africa. Drugs used for treatment against HAT first stage have limited effectiveness, and the second stage drugs have been reported to be toxic, expensive, and have time-consuming administration, and parasitic resistance has developed against these drugs. The aim of this study was to evaluate the anti-trypanosomal activity of nitrofurantoin-triazole hybrids against T. b. gambiense and T. b. rhodesiense parasites in vitro. This study screened 19 synthesized nitrofurantoin-triazole (NFT) hybrids on two strains of human trypanosomes, and cytotoxicity was evaluated on Madin-Darby bovine kidney (MDBK) cells. The findings in this study showed that an increase in the chain length and the number of carbon atoms in some n-alkyl hybrids influenced the increase in anti-trypanosomal activity against T. b. gambiense and T. b. rhodesiense. The short-chain n-alkyl hybrids showed decreased activity compared to the long-chain n-alkyl hybrids, with increased activity against both T. b. gambiense and T. b. rhodesiense. Incorporation of additional electron-donating substituents in some NFT hybrids showed increased anti-trypanosomal activity than to electron-withdrawing substituents in NFT hybrids. All 19 NFT hybrids tested displayed better anti-trypanosomal activity against T. b. gambiense than T. b. rhodesiense. The NFT hybrid no. 16 was among the best performing hybrids against both T. b. gambiense (0.08 ± 0.04 μM) and T. b.rhodesiense (0.11 ± 0.06 μM), and its activity might be influenced by the introduction of fluorine in the para-position on the benzyl ring. Remarkably, the NFT hybrids in this study displayed weak to moderate cytotoxicity on MDBK cells. All of the NFT hybrids in this study had selectivity index values ranging from 18 to greater than 915, meaning that they were up to 10–100 times fold selective in their anti-trypanosomal activity. The synthesized NFT hybrids showed strong selectivity >10 to T. b. gambiense and T. b. rhodesiense, which indicates that they qualify from the initial selection criteria for potential hit drugs.
人类非洲锥虫病（HAT）又称昏睡病，由流行于非洲西部和中部的布氏锥虫和流行于非洲东部和南部的罗得西亚锥虫引起。用于治疗 HAT 第一阶段的药物效果有限，第二阶段的药物据报道毒性大、价格昂贵、用药耗时，而且寄生虫对这些药物产生了抗药性。本研究的目的是评估硝基呋喃妥因-三唑混合物在体外对冈比亚锥虫和罗得西亚锥虫的抗锥虫活性。本研究筛选了 19 种合成的硝基呋喃妥因-三唑（NFT）混合物对两株人类锥虫的作用，并评估了它们对马丁达比牛肾细胞（MDBK）的细胞毒性。研究结果表明，一些正烷基杂交化合物链长和碳原子数的增加会影响其对冈比亚锥虫和罗得西亚锥虫抗锥虫活性的提高。与长链正烷基杂交体相比，短链正烷基杂交体的活性降低，而对冈比亚锥虫和罗得西亚锥虫的活性提高。在一些 NFT 杂交化合物中加入额外的电子供能取代基后，其抗锥虫活性比 NFT 杂交化合物中的电子吸收取代基更强。测试的 19 种 NFT 杂交种对冈比亚锥虫的抗锥虫活性均优于对罗得西亚锥虫的抗锥虫活性。第 16 号 NFT 杂交种对 T. b. gambiense（0.08 ± 0.04 μM）和 T. b. rhodesiense（0.11 ± 0.06 μM）的抗锥虫活性都是最好的，其活性可能受到在苄基环的对位上引入氟的影响。值得注意的是，本研究中的 NFT 杂交化合物对 MDBK 细胞显示出弱至中等的细胞毒性。本研究中的所有 NFT 杂交化合物的选择性指数值从 18 到大于 915 不等，这意味着它们在抗锥虫活性方面的选择性高达 10-100 倍。合成的NFT杂交种对冈比亚锥虫和罗得西亚锥虫的选择性大于10，这表明它们符合潜在靶向药物的初步筛选标准。
{"title":"In vitro anti-trypanosomal activity of synthetic nitrofurantoin-triazole hybrids against Trypanosoma species causing human African trypanosomosis","authors":"Anna Seetsi, David D. N'da, Nthatisi Molefe-Nyembe, Keisuke Suganuma, Tsepo Ramatla, Oriel Thekisoe","doi":"10.1111/fcp.12940","DOIUrl":"10.1111/fcp.12940","url":null,"abstract":"<p>Human African trypanosomosis (HAT) which is also known as sleeping sickness is caused by <i>Trypanosoma brucei gambiense</i> that is endemic in western and central Africa and <i>T. b. rhodesiense</i> that is endemic in eastern and southern Africa. Drugs used for treatment against HAT first stage have limited effectiveness, and the second stage drugs have been reported to be toxic, expensive, and have time-consuming administration, and parasitic resistance has developed against these drugs. The aim of this study was to evaluate the anti-trypanosomal activity of nitrofurantoin-triazole hybrids against <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i> parasites in vitro. This study screened 19 synthesized nitrofurantoin-triazole (NFT) hybrids on two strains of human trypanosomes, and cytotoxicity was evaluated on Madin-Darby bovine kidney (MDBK) cells. The findings in this study showed that an increase in the chain length and the number of carbon atoms in some n-alkyl hybrids influenced the increase in anti-trypanosomal activity against <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i>. The short-chain n-alkyl hybrids showed decreased activity compared to the long-chain n-alkyl hybrids, with increased activity against both <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i>. Incorporation of additional electron-donating substituents in some NFT hybrids showed increased anti-trypanosomal activity than to electron-withdrawing substituents in NFT hybrids. All 19 NFT hybrids tested displayed better anti-trypanosomal activity against <i>T. b. gambiense</i> than <i>T. b. rhodesiense</i>. The NFT hybrid no. 16 was among the best performing hybrids against both <i>T. b. gambiense</i> (0.08 ± 0.04 μM) and <i>T. b.rhodesiense</i> (0.11 ± 0.06 μM), and its activity might be influenced by the introduction of fluorine in the para-position on the benzyl ring. Remarkably, the NFT hybrids in this study displayed weak to moderate cytotoxicity on MDBK cells. All of the NFT hybrids in this study had selectivity index values ranging from 18 to greater than 915, meaning that they were up to 10–100 times fold selective in their anti-trypanosomal activity. The synthesized NFT hybrids showed strong selectivity >10 to <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i>, which indicates that they qualify from the initial selection criteria for potential hit drugs.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.12940","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9955223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Helmi Ammar, Christine Le Beller, Didier Bouccara, David Malinvaud, Romain Jouffroy, Agnès Lillo-Le Louet
Background
There are few publications regarding manifestations of vestibular disorders (VDs) following BNT162b2 mRNA COVID-19 vaccination.
Purpose
We describe cases of VD potentially related to BNT162b2 vaccination and calculate its reporting rate, in order to enlarge knowledge about this adverse effect.
Methods
A retrospective analysis of cases of VD following BNT162b2 vaccination reported to the pharmacovigilance centre of Georges-Pompidou European Hospital (France), in 2021 was performed. In order to identify these cases from the pharmacovigilance database containing all our registered cases, we used the Standardised MedDRA Query (SMQ) ‘vestibular disorders’. Then we analysed cases with vestibular symptoms, based on the association of typical manifestations. The reporting rate was calculated based on the number of VD cases and the number of vaccinated patients.
Results
Among 6608 cases reported to our centre related to COVID-19 vaccines during 2021, 34 VDs associated with BNT162b2 administration were included. They were mainly reported in females (79%), 62% occurred after the first dose and 32% were serious. Symptoms had completely resolved in 13 cases (38%). Vertigo was the most common symptom followed by balance disorders. Three patients received second dose without reappearance of VD. The final diagnosis was reported in 10 patients (six cases of vestibular neuritis, two cases of central VD, two cases of benign paroxysmal positional vertigo). The regional reporting rate was 26 [95% CI: 17–34] cases of VD per 1 million persons vaccinated.
Conclusion
Although the relationship between vaccination and VD cannot be established, clinicians should be aware of this rare adverse effect.
{"title":"Vestibular disorders following BNT162b2 mRNA COVID-19 vaccination: A retrospective case series","authors":"Helmi Ammar, Christine Le Beller, Didier Bouccara, David Malinvaud, Romain Jouffroy, Agnès Lillo-Le Louet","doi":"10.1111/fcp.12942","DOIUrl":"10.1111/fcp.12942","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>There are few publications regarding manifestations of vestibular disorders (VDs) following BNT162b2 mRNA COVID-19 vaccination.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>We describe cases of VD potentially related to BNT162b2 vaccination and calculate its reporting rate, in order to enlarge knowledge about this adverse effect.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A retrospective analysis of cases of VD following BNT162b2 vaccination reported to the pharmacovigilance centre of Georges-Pompidou European Hospital (France), in 2021 was performed. In order to identify these cases from the pharmacovigilance database containing all our registered cases, we used the Standardised MedDRA Query (SMQ) ‘vestibular disorders’. Then we analysed cases with vestibular symptoms, based on the association of typical manifestations. The reporting rate was calculated based on the number of VD cases and the number of vaccinated patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 6608 cases reported to our centre related to COVID-19 vaccines during 2021, 34 VDs associated with BNT162b2 administration were included. They were mainly reported in females (79%), 62% occurred after the first dose and 32% were serious. Symptoms had completely resolved in 13 cases (38%). Vertigo was the most common symptom followed by balance disorders. Three patients received second dose without reappearance of VD. The final diagnosis was reported in 10 patients (six cases of vestibular neuritis, two cases of central VD, two cases of benign paroxysmal positional vertigo). The regional reporting rate was 26 [95% CI: 17–34] cases of VD per 1 million persons vaccinated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Although the relationship between vaccination and VD cannot be established, clinicians should be aware of this rare adverse effect.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9900153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer cachexia is a debilitating syndrome associated with marked body loss because of muscular atrophy and fat loss. There are several mechanisms contributing to the pathogenesis of cachexia. The presence of the tumor releases cytokines from inflammatory and immune cells, which play a significant role in activating and deactivating certain pathways associated with protein, carbohydrate, and lipid metabolism. This review focuses on various cascades involving an imbalance between protein synthesis and degradation in the skeletal muscles.
Objectives
This study aimed to elucidate the mechanisms involved in skeletal muscle wasting phenomenon over the last few years.
Methods
This article briefly overviews different pathways responsible for muscle atrophy in cancer cachexia. Studies published up to April 2023 were included. Important findings and study contributions were chosen and compiled using several databases including PubMed, Google Scholar, Science Direct, and ClinicalTrials.gov using relevant keywords.
Results
Cancer cachexia is a complex disease involving multiple factors resulting in atrophy of skeletal muscles. Systemic inflammation, altered energy balance and carbohydrate metabolism, altered lipid and protein metabolism, and adipose tissue browning are some of the major culprits in cancer cachexia. Increased protein degradation and decreased protein synthesis lead to muscle atrophy. Changes in signaling pathway like ubiquitin-proteasome, autophagy, mTOR, AMPK, and IGF-1 also lead to muscle wasting. Physical exercise, nutritional supplementation, steroids, myostatin inhibitors, and interventions targeting on inflammation have been investigated to treat cancer cachexia. Some therapy showed positive results in preclinical and clinical settings, although more research on the efficacy and safety of the treatment should be done.
Conclusion
Muscle atrophy in cancer cachexia is the result of multiple complex mechanisms; as a result, a lot more research has been done to describe the pathophysiology of the disease. Targeted therapy and multimodal interventions can improve clinical outcomes for patients.
{"title":"Deliberation on debilitating condition of cancer cachexia: Skeletal muscle wasting","authors":"Srusti Dave, Bhoomika M. Patel","doi":"10.1111/fcp.12931","DOIUrl":"10.1111/fcp.12931","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer cachexia is a debilitating syndrome associated with marked body loss because of muscular atrophy and fat loss. There are several mechanisms contributing to the pathogenesis of cachexia. The presence of the tumor releases cytokines from inflammatory and immune cells, which play a significant role in activating and deactivating certain pathways associated with protein, carbohydrate, and lipid metabolism. This review focuses on various cascades involving an imbalance between protein synthesis and degradation in the skeletal muscles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study aimed to elucidate the mechanisms involved in skeletal muscle wasting phenomenon over the last few years.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This article briefly overviews different pathways responsible for muscle atrophy in cancer cachexia. Studies published up to April 2023 were included. Important findings and study contributions were chosen and compiled using several databases including PubMed, Google Scholar, Science Direct, and ClinicalTrials.gov using relevant keywords.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Cancer cachexia is a complex disease involving multiple factors resulting in atrophy of skeletal muscles. Systemic inflammation, altered energy balance and carbohydrate metabolism, altered lipid and protein metabolism, and adipose tissue browning are some of the major culprits in cancer cachexia. Increased protein degradation and decreased protein synthesis lead to muscle atrophy. Changes in signaling pathway like ubiquitin-proteasome, autophagy, mTOR, AMPK, and IGF-1 also lead to muscle wasting. Physical exercise, nutritional supplementation, steroids, myostatin inhibitors, and interventions targeting on inflammation have been investigated to treat cancer cachexia. Some therapy showed positive results in preclinical and clinical settings, although more research on the efficacy and safety of the treatment should be done.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Muscle atrophy in cancer cachexia is the result of multiple complex mechanisms; as a result, a lot more research has been done to describe the pathophysiology of the disease. Targeted therapy and multimodal interventions can improve clinical outcomes for patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9835858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Senthilathiban Daisy Precilla, Shreyas S. Kuduvalli, Indrani Biswas, Krishnamurthy Bhavani, Agieshkumar Balakrishna Pillai, Jisha Mary Thomas, Thirugnanasambandhar Sivasubramanian Anitha
Background
Glioblastomas arise from multistep tumorigenesis of the glial cells. Despite the current state-of-art treatment, tumor recurrence is inevitable. Among the innovations blooming up against glioblastoma, drug repurposing could provide profound premises for treatment enhancement. While considering this strategy, the efficacy of the repurposed drugs as monotherapies were not up to par; hence, the focus has now shifted to investigate the multidrug combinations.
Aim
To investigate the efficacy of a quadruple-combinatorial treatment comprising temozolomide along with chloroquine, naringenin, and phloroglucinol in an orthotopic glioma-induced xenograft model.
Methods
Antiproliferative effect of the drugs was assessed by immunostaining. The expression profiles of WNT/β-catenin and apoptotic markers were evaluated by qRT-PCR, immunoblotting, and ELISA. Patterns of mitochondrial depolarization was determined by flow cytometry. TUNEL assay was performed to affirm apoptosis induction. In vivo drug detection study was carried out by ESI-Q-TOF MS analysis.
Results
The quadruple-drug treatment had significantly hampered glioma proliferation and had induced apoptosis by modulating the WNT/β-catenin signaling. Interestingly, the induction of apoptosis was associated with mitochondrial depolarization. The quadruple-drug cocktail had breached the blood–brain barrier and was detected in the brain tissue and plasma samples.
Conclusion
The quadruple-drug combination served as a promising adjuvant therapy to combat glioblastoma lethality in vivo and can be probed for translation from bench to bedside.
{"title":"Repurposing synthetic and natural derivatives induces apoptosis in an orthotopic glioma-induced xenograft model by modulating WNT/β-catenin signaling","authors":"Senthilathiban Daisy Precilla, Shreyas S. Kuduvalli, Indrani Biswas, Krishnamurthy Bhavani, Agieshkumar Balakrishna Pillai, Jisha Mary Thomas, Thirugnanasambandhar Sivasubramanian Anitha","doi":"10.1111/fcp.12932","DOIUrl":"10.1111/fcp.12932","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Glioblastomas arise from multistep tumorigenesis of the glial cells. Despite the current state-of-art treatment, tumor recurrence is inevitable. Among the innovations blooming up against glioblastoma, drug repurposing could provide profound premises for treatment enhancement. While considering this strategy, the efficacy of the repurposed drugs as monotherapies were not up to par; hence, the focus has now shifted to investigate the multidrug combinations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To investigate the efficacy of a quadruple-combinatorial treatment comprising temozolomide along with chloroquine, naringenin, and phloroglucinol in an orthotopic glioma-induced xenograft model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Antiproliferative effect of the drugs was assessed by immunostaining. The expression profiles of WNT/β-catenin and apoptotic markers were evaluated by qRT-PCR, immunoblotting, and ELISA. Patterns of mitochondrial depolarization was determined by flow cytometry. TUNEL assay was performed to affirm apoptosis induction. In vivo drug detection study was carried out by ESI-Q-TOF MS analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The quadruple-drug treatment had significantly hampered glioma proliferation and had induced apoptosis by modulating the WNT/β-catenin signaling. Interestingly, the induction of apoptosis was associated with mitochondrial depolarization. The quadruple-drug cocktail had breached the blood–brain barrier and was detected in the brain tissue and plasma samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The quadruple-drug combination served as a promising adjuvant therapy to combat glioblastoma lethality in vivo and can be probed for translation from bench to bedside.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2023-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9781763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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