scholarly journals Apomorphine induces mitochondrial-dysfunction-dependent apoptosis in choriocarcinoma

Reproduction ◽  
2020 ◽  
Vol 160 (3) ◽  
pp. 367-377
Author(s):  
Jin-Young Lee ◽  
Jiyeon Ham ◽  
Whasun Lim ◽  
Gwonhwa Song
Keyword(s):  
Molecular Mechanisms ◽  
Drug Repositioning ◽  
Synergistic Effects ◽  
Therapeutic Effects ◽  
Antitumor Effects ◽  
Apoptosis Pathway ◽  
Atp Production ◽  
Intrinsic Apoptosis Pathway ◽  
Choriocarcinoma Cells ◽  
Energy Deprivation

Apomorphine is a derivative of morphine that is used for the treatment of Parkinson’s disease because of its effects on the hypothalamus. Therapeutic effects of apomorphine have also been reported for various neurological diseases and cancers. However, the molecular mechanisms of the antitumor effects of apomorphine are not clear, especially with respect to choriocarcinoma. This is the first study to elucidate the anticancer effects of apomorphine on choriocarcinoma. We found that apomorphine suppressed the viability, proliferation, ATP production, and spheroid formation of JEG3 and JAR choriocarcinoma cells. Moreover, apomorphine activated the intrinsic apoptosis pathway by activating caspases and inhibited the production of anti-apoptotic proteins in choriocarcinoma cells. Further, apomorphine caused depolarization of mitochondria, calcium overload, energy deprivation, and endoplasmic reticulum stress in JEG3 and JAR cells. We confirmed synergistic effects of apomorphine with paclitaxel, a traditional chemotherapeutic agent, and propose that apomorphine could be a potential therapeutic agent in choriocarcinoma and an important candidate for drug repositioning that could help overcome resistance to conventional chemotherapy.

scholarly journals Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Simeng Zhang ◽  
Zhongyan Hua ◽  
Gen Ba ◽  
Ning Xu ◽  
Jianing Miao ◽  
...  
Keyword(s):  
Cell Death ◽  
Synergistic Effects ◽  
Aerobic Glycolysis ◽  
Single Agent ◽  
Molecular Compound ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Atp Production

Abstract Background Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. Methods We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. Results When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. Conclusions The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.

scholarly journals Advancing Drug Discovery and Development from Active Constituents of Yinchenhao Tang, a Famous Traditional Chinese Medicine Formula

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Aihua Zhang ◽  
Hui Sun ◽  
Shi Qiu ◽  
Xijun Wang
Keyword(s):  
Systems Biology ◽  
Drug Discovery ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Molecular Mechanisms ◽  
Synergistic Effects ◽  
Molecular Networks ◽  
Agile Development ◽  
Therapeutic Effects ◽  
Systematic Analysis

Traditional Chinese medicine (TCM) formula has been playing a very important role in health protection and disease control for thousands of years. Guided by TCM syndrome theories, formula are designed to contain a combination of various kinds of crude drugs that, when combined, will achieve synergistic efficacy. However, the precise mechanism of synergistic action remains poorly understood. One example is a famous TCM formula Yinchenhao Tang (YCHT), whose efficacy in treating hepatic injury (HI) and Jaundice syndrome, has recently been well established as a case study. We also conducted a systematic analysis of synergistic effects of the principal compound using biochemistry, pharmacokinetics and systems biology, to explore the key molecular mechanisms. We had found that the three component (6,7-dimethylesculetin (D), geniposide (G), and rhein (R)) combination exerts a more robust synergistic effect than any one or two of the three individual compounds by hitting multiple targets. They can regulate molecular networks through activating both intrinsic and extrinsic pathways to synergistically cause intensified therapeutic effects. This paper provides an overview of the recent and potential developments of chemical fingerprinting coupled with systems biology advancing drug discovery towards more agile development of targeted combination therapies for the YCHT.

scholarly journals A Network Pharmacology Approach to Uncover the Molecular Mechanisms of Herbal Formula Ban-Xia-Xie-Xin-Tang

2018 ◽  
Vol 2018 ◽  
pp. 1-22 ◽  
Author(s):  
Ming Yang ◽  
Jialei Chen ◽  
Liwen Xu ◽  
Xiufeng Shi ◽  
Xin Zhou ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Synergistic Effects ◽  
Network Pharmacology ◽  
Disease Genes ◽  
Traditional Theory ◽  
Therapeutic Effects ◽  
Proximity Analysis ◽  
Path Distance ◽  
Therapeutic Mechanisms ◽  
Shortest Path Distance

Ban-Xia-Xie-Xin-Tang (BXXXT) is a classical formula from Shang-Han-Lun which is one of the earliest books of TCM clinical practice. In this work, we investigated the therapeutic mechanisms of BXXXT for the treatment of multiple diseases using a network pharmacology approach. Here three BXXXT representative diseases (colitis, diabetes mellitus, and gastric cancer) were discussed, and we focus on in silico methods that integrate drug-likeness screening, target prioritizing, and multilayer network extending. A total of 140 core targets and 72 representative compounds were finally identified to elucidate the pharmacology of BXXXT formula. After constructing multilayer networks, a good overlap between BXXXT nodes and disease nodes was observed at each level, and the network-based proximity analysis shows that the relevance between the formula targets and disease genes was significant according to the shortest path distance (SPD) and a random walk with restart (RWR) based scores for each disease. We found that there were 22 key pathways significantly associated with BXXXT, and the therapeutic effects of BXXXT were likely addressed by regulating a combination of targets in a modular pattern. Furthermore, the synergistic effects among BXXXT herbs were highlighted by elucidating the molecular mechanisms of individual herbs, and the traditional theory of “Jun-Chen-Zuo-Shi” of TCM formula was effectively interpreted from a network perspective. The proposed approach provides an effective strategy to uncover the mechanisms of action and combinatorial rules of BXXXT formula in a holistic manner.

scholarly journals Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 188
Author(s):  
Brigitte Bauvois ◽  
Elodie Pramil ◽  
Ludovic Jondreville ◽  
Claire Quiney ◽  
Florence Nguyen-Khac ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Survival ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Lymphocytic Leukemia ◽  
Type I ◽  
Apoptosis Resistance ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

Besides their antiviral and immunomodulatory functions, type I (α/β) and II (γ) interferons (IFNs) exhibit either beneficial or detrimental effects on tumor progression. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal CD5+ B lymphocytes that escape death. Drug resistance and disease relapse still occur in CLL. The triggering of IFN receptors is believed to be involved in the survival of CLL cells, but the underlying molecular mechanisms are not yet characterized. We show here that both type I and II IFNs promote the survival of primary CLL cells by counteracting the mitochondrial (intrinsic) apoptosis pathway. The survival process was associated with the upregulation of signal transducer and activator of transcription-3 (STAT3) and its target anti-apoptotic Mcl-1. Furthermore, the blockade of the STAT3/Mcl-1 pathway by pharmacological inhibitors against STAT3, TYK2 (for type I IFN) or JAK2 (for type II IFN) markedly reduced IFN-mediated CLL cell survival. Similarly, the selective Src family kinase inhibitor PP2 notably blocked IFN-mediated CLL cell survival by downregulating the protein levels of STAT3 and Mcl-1. Our work reveals a novel mechanism of resistance to apoptosis promoted by IFNs in CLL cells, whereby JAKs (TYK2, JAK2) and Src kinases activate in concert a STAT3/Mcl-1 signaling pathway. In view of current clinical developments of potent STAT3 and Mcl-1 inhibitors, a combination of conventional treatments with these inhibitors might thus constitute a new therapeutic strategy in CLL.

A Network Pharmacology Analysis of the Systems-Perspective Anticancer Mechanisms of the Herbal Drug FDY2004 for Breast Cancer

2021 ◽  
Vol 16 (10) ◽  
pp. 1934578X2110491
Author(s):  
Ho-Sung Lee ◽  
In-Hee Lee ◽  
Kyungrae Kang ◽  
Sang-In Park ◽  
Tae-Wook Kwon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Therapeutic Effects ◽  
Herbal Drugs ◽  
Apoptosis Pathway ◽  
Anticancer Properties ◽  
Systems Perspective

Breast cancer is a malignant tumor with high incidence, prevalence, and mortality rates in women. In recent years, herbal drugs have been assessed as anticancer therapy against breast cancer, owing to their promising therapeutic effects and reduced toxicity. However, their pharmacological mechanisms have not been fully explored at the systemic level. Here, we conducted a network pharmacology analysis of the systems-perspective molecular mechanisms of FDY2004, an anticancer herbal formula that consists of Moutan Radicis Cortex, Persicae Semen , and Rhei Radix et Rhizoma, against breast cancer. We determined that FDY2004 may contain 28 active compounds that exert pharmacological effects by targeting 113 breast cancer-related human genes/proteins. Based on the gene ontology terms, the FDY2004 targets were involved in modulating biological processes such as cell growth, cell proliferation, and apoptosis. Pathway enrichment analysis identified various breast cancer-associated pathways that may mediate the anticancer activity of FDY2004, including the PI3K-Akt, MAPK, TNF, HIF-1, focal adhesion, estrogen, ErbB, NF-kappa B, p53, and VEGF signaling pathways. Thus, our analysis offers novel insights into the anticancer properties of herbal drugs for breast cancer treatment from a systemic perspective.

Influence of Ca2+ on mitochondrial apoptosis activation and yak meat tenderization during postmortem aging

2021 ◽  
pp. 1-12
Author(s):  
Lin-lin Wang ◽  
Lian-hong Chen ◽  
Jian Li ◽  
Rong-sheng Du ◽  
Ling Han ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Citrate Synthase ◽  
Control Group ◽  
Mitochondrial Apoptosis ◽  
Apoptosis Pathway ◽  
Atp Production ◽  
Mitochondrial Apoptosis Pathway ◽  
Mitochondrial Functions ◽  
Postmortem Aging ◽  
Meat Tenderization

The objective of this study was to investigate the underlying molecular mechanisms of mitochondrial Ca2+ homeostasis disequilibrium in mitochondrial apoptosis and its impact on yak meat tenderness. Results indicated that CaCl2 treatment significantly promoted glycolysis by increasing lactic acid level and decreasing glycogen content, pH, and ATP production (P < 0.01 and P < 0.05). The activities of Na+-K+-ATPase pump and Ca2+-ATPase pump in the early aging stage were significantly influenced by CaCl2 treatment. The activities of synchronous digital hierarchy and citrate synthase were also significantly improved by CaCl2 treatment (P < 0.01 and P < 0.05). Mitochondrial reactive oxygen species (ROS) levels were significantly higher in the CaCl2 group than in the control group (P < 0.01); at 24 h, the value in the Ca2+ group was 64.27% higher than that in the control group. Furthermore, CaCl2 treatment significantly enhanced the mitochondrial apoptosis cascade reaction and meat tenderization by improving the myofibril fragmentation index and shear force (P < 0.01). These results demonstrated that the imbalance of mitochondrial Ca2+ homeostasis played a significant role in the mitochondrial apoptosis pathway by regulating energy metabolism factors, meat intracellular environment, mitochondrial functions, and ROS-mediated oxidative stress. These conditions further improved meat tenderization during postmortem aging.

Synergistic activity of vertical combinations of agents targeting multiple steps along the RAF/MEK/ERK cascade as a therapeutic strategy in human tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13572-e13572 ◽  
Author(s):  
Ursula Cesta Incani ◽  
Anais Del Curatolo ◽  
Cristina Di Sanza ◽  
Italia Falcone ◽  
Francesco Cognetti ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Molecular Mechanisms ◽  
Synergistic Effects ◽  
Braf V600e ◽  
Fixed Dose ◽  
Synergistic Activity ◽  
Dose Ratio ◽  
Antitumor Effects ◽  
Mapk Activation ◽  
A549 Lung

e13572 Background: BRAF-selective kinase inhibitors have potent antitumor effects in mutant BRAF(V600E) tumors; however, in BRAF-wt cells, they paradoxically activate MEK/ERK. In addition, MEK blockade may induce compensatory signaling through both upstream pathway elements (RAF) and parallel pathways (PI3K/AKT/mTOR). Methods: We set out to define molecular and functional effects of single and combined BRAF (GSK2118436A, BRAF-I) and MEK (GSK1120212B, MEK-I) inhibition, using WB analysis to dissect signaling and a fixed dose-ratio experimental design to assess functional synergism by conservative isobologram analysis. Results: In A549 lung adenocarcinoma (KRAS G12S), BRAF-I (10 μM) induces hyperphosphorylation of CRAF, MEK, ERK, and p90RSK, while MEK-I (10 nM), alone or in combination with BRAF-I, potently offsets MAPK activation. Combined BRAF-I and MEK-I suppress malignant growth and survival at 72 h with highly synergistic effects in the A549 (lung, KRAS G12S), H1299 (lung, NRAS), HCT116 (colon, KRAS G13D), and MIAPACA (pancreatic, KRAS G12V) models, with combination indexes (CI), ranging from 1.37 to 0.12. Conversely, in other lung cancer models (H460, Calu-1, Calu-3) the combination of BRAF-I and MEK-I produced modestly additive to highly antagonistic antitumor effects. In BRAF-mutant melanoma and colon carcinoma models (M14 and HT29), there was no paradoxical activation of the MEK/ERK module in response to BRAF-I and both BRAF-I and MEK-I had pronounced growth inhibitory effects as single agents, but were frankly antagonistic in combination. Similarly, the pan-RAF inhibitor RAF265 did not cause MAPK activation and did not result in synergistic growth inhibition when combined with the MEK-I in the A549 and MIAPACA cell lines. Conclusions: Overall, our data indicate that combined inhibition of multiple signaling elements along the RAF/MEK/ERK pathway results in strongly synergistic growth inhibition, particularly in tumors with RAS mutations. Additional studies to better define genetic determinants of sensitivity/resistance and molecular mechanisms of therapeutic synergism of combined BRAF-I and MEK-I are currently ongoing.

Computational drug repositioning based on the relationships between substructure–indication

2020 ◽  
Author(s):  
Jingbo Yang ◽  
Denan Zhang ◽  
Lei Liu ◽  
Guoqi Li ◽  
Yiyang Cai ◽  
...  
Keyword(s):  
Drug Target ◽  
Drug Repositioning ◽  
Structural Similarity ◽  
Antiviral Effect ◽  
Therapeutic Effects ◽  
Apoptosis Pathway ◽  
Local Structures ◽  
Verification Methods ◽  
Trisphosphate Receptor ◽  
First Time

Abstract At present, computational methods for drug repositioning are mainly based on the whole structures of drugs, which limits the discovery of new functions due to the similarities between local structures of drugs. In this article, we, for the first time, integrated the features of chemical-genomics (substructure–domain) and pharmaco-genomics (domain–indication) based on the assumption that drug–target interactions are mediated by the substructures of drugs and the domains of proteins to identify the relationships between substructure–indication and establish a drug–substructure–indication network for predicting all therapeutic effects of tested drugs through only information on the substructures of drugs. In total, 83 205 drug–indication relationships with different correlation scores were obtained. We used three different verification methods to indicate the accuracy of the method and the reliability of the scoring system. We predicted all indications of olaparib using our method, including the known antitumor effect and unknown antiviral effect verified by literature, and we also discovered the inhibitory mechanism of olaparib toward DNA repair through its specific sub494 (o = C–C: C), as it participates in the low synthesis of the poly subfunction of the apoptosis pathway (hsa04210) by inhibiting the Inositol 1,4,5-trisphosphate receptor(s) (ITPRs) and hydrolyzing poly (ADP ribose) polymerases. ElectroCardioGrams of four drugs (quinidine, amiodarone, milrinone and fosinopril) demonstrated the effect of anti-arrhythmia. Unlike previous studies focusing on the overall structures of drugs, our research has great potential in the search for more therapeutic effects of drugs and in predicting all potential effects and mechanisms of a drug from the local structural similarity.

scholarly journals Baicalin Induces Apoptosis and Suppresses the Cell Cycle Progression of Lung Cancer Cells Through Downregulating Akt/mTOR Signaling Pathway

2021 ◽  
Vol 7 ◽  
Author(s):  
Xinbing Sui ◽  
Xuemeng Han ◽  
Peng Chen ◽  
Qibiao Wu ◽  
Jiao Feng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Antitumor Activity ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Therapeutic Effects ◽  
Antitumor Effects ◽  
Beneficial Effects ◽  
Cycle Arrest

Baicalin, as a natural active ingredient extracted and isolated from the traditional Chinese medicine Scutellaria baicalensis Georgi., has been potentially used in various areas for its antioxidative, antitumor, anti-inflammatory, and anti-proliferative activities. Although several studies have reported the antitumor effects of baicalin against various cancer types, its beneficial effects on lung cancer have not yet been elucidated. Therefore, the therapeutic effects and molecular mechanisms of baicalin on lung cancer cell lines H1299 and H1650 were investigated. Here, the results of its antitumor activity were shown. We found that Akt/mTOR pathway inhibition was the essential determinant in baicalin-induced cell cycle arrest. Furthermore, when the Akt Agonist SC79 or Akt plasmid transfection was performed, the antitumor effect of baicalin was significantly abrogated in both H1299 and H1650 cells. In conclusion, we found that baicalin exerted its antitumor activity mainly by inducing Akt-dependent cell cycle arrest and promoting apoptosis, which show great potential for developing a new drug for lung cancer treatment.

scholarly journals Biological Activity of Lenalidomide and Its Underlying Therapeutic Effects in Multiple Myeloma

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Roberta Martiniani ◽  
Valentina Di Loreto ◽  
Chiara Di Sano ◽  
Alessandra Lombardo ◽  
Anna Marina Liberati
Keyword(s):  
Multiple Myeloma ◽  
Chemical Structure ◽  
Molecular Mechanisms ◽  
Hematologic Malignancies ◽  
Review Article ◽  
Therapeutic Effects ◽  
Immunomodulatory Drugs ◽  
Antitumor Effects ◽  
Synthetic Compound ◽  
Pleiotropic Properties

Lenalidomide is a synthetic compound derived by modifying the chemical structure of thalidomide. It belongs to the second generation of immunomodulatory drugs (IMiDs) and possesses pleiotropic properties. Even if lenalidomide has been shown to be active in the treatment of several hematologic malignancies, this review article is mostly focalized on its mode of action in multiple myeloma. The present paper is about the direct and indirect antitumor effects of lenalidomide on malignant plasmacells, bone marrow microenvironment, bone resorption and host’s immune response. The molecular mechanisms and targets of lenalidomide remain largely unknown, but recent evidence shows cereblon (CRBN) as a possible mediator of its therapeutical effects.

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