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Article ; Online: Capsaicin Targets Lipogenesis in HepG2 Cells Through AMPK Activation, AKT Inhibition and PPARs Regulation.

Bort, Alicia / Sánchez, Belén G / Mateos-Gómez, Pedro A / Díaz-Laviada, Inés / Rodríguez-Henche, Nieves

International journal of molecular sciences

2019 Volume 20, Issue 7

Abstract: Obesity, a major risk factor for chronic diseases such as type 2 diabetes (T2D), represents a serious primary health problem worldwide. Dietary habits are of special interest to prevent and counteract the obesity and its associated metabolic disorders, ... ...

Abstract	Obesity, a major risk factor for chronic diseases such as type 2 diabetes (T2D), represents a serious primary health problem worldwide. Dietary habits are of special interest to prevent and counteract the obesity and its associated metabolic disorders, including lipid steatosis. Capsaicin, a pungent compound of chili peppers, has been found to ameliorate diet-induced obesity in rodents and humans. The purpose of this study was to examine the effect of capsaicin on hepatic lipogenesis and to delineate the underlying signaling pathways involved, using HepG2 cells as an experimental model. Cellular neutral lipids, stained with BODIPY493/503, were quantified by flow cytometry, and the protein expression and activity were determined by immunoblotting. Capsaicin reduced basal neutral lipid content in HepG2 cells, as well that induced by troglitazone or by oleic acid. This effect of capsaicin was prevented by dorsomorphin and GW9662, pharmacological inhibitors of AMPK and PPARγ, respectively. In addition, capsaicin activated AMPK and inhibited the AKT/mTOR pathway, major regulators of hepatic lipogenesis. Furthermore, capsaicin blocked autophagy and increased PGC-1α protein. These results suggest that capsaicin behaves as an anti-lipogenic compound in HepG2 cells.
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Autophagy/drug effects ; Capsaicin/pharmacology ; Enzyme Activation/drug effects ; Hep G2 Cells ; Humans ; Lipids/analysis ; Lipogenesis/drug effects ; Models, Biological ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Peroxisome Proliferator-Activated Receptors/metabolism ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/metabolism ; Up-Regulation/drug effects
Chemical Substances	Lipids ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Peroxisome Proliferator-Activated Receptors ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Capsaicin (S07O44R1ZM)
Language	English
Publishing date	2019-04-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20071660
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase.

Sánchez, Belén G / Bort, Alicia / Mateos-Gómez, Pedro A / Rodríguez-Henche, Nieves / Díaz-Laviada, Inés

Cancer cell international

2019 Volume 19, Page(s) 54

Abstract: Background: Current chemotherapy for castration-resistant prostate cancer is established on taxane-based compounds like docetaxel. However, eventually, the development of toxic side effects and resistance limits the therapeutic benefit being the major ... ...

Abstract	Background: Current chemotherapy for castration-resistant prostate cancer is established on taxane-based compounds like docetaxel. However, eventually, the development of toxic side effects and resistance limits the therapeutic benefit being the major concern in the treatment of prostate cancer. Combination therapies in many cases, enhance drug efficacy and delay the appearance of undesired effects, representing an important option for the treatment of castration-resistant prostate cancer. In this study, we tested the efficacy of the combination of docetaxel and capsaicin, the pungent ingredient of hot chili peppers, on prostate cancer cells proliferation. Methods: Prostate cancer LNCaP and PC3 cell lines were used in this study. Levels of total and phosphorylated forms of Akt, mTOR, S6, LKB1, AMPK and ACC were determined by Western blot. AMPK, LKB1 and Akt knock down was performed by siRNA. PTEN was overexpressed by transient transfection with plasmids. Xenograft prostate tumors were induced in nude mice and treatments (docetaxel and capsaicin) were administered intraperitoneally. Statistical analyses were performed with GraphPad software. Combination index was calculated with Compusyn software. Results: Docetaxel and capsaicin synergistically inhibited the growth of LNCaP and PC3 cells, with a combination index lower than 1 for most of the combinations tested. Co-treatment with docetaxel and capsaicin notably decreased Akt and its downstream targets mTOR and S6 phosphorylation. Overexpression of PTEN phosphatase abrogated the synergistic antiproliferative effect of docetaxel and capsaicin. The combined treatment also increased the phosphorylation of AMP-activated kinase (AMPK) and the phosphorylation of its substrate ACC. In addition, pharmacological inhibition of AMPK with dorsomorphin (compound C) as well as knock down by siRNA of AMPK or its upstream kinase LKB1, abolished the synergy of docetaxel and capsaicin. Mechanistically, we showed that the synergistic anti-proliferative effect may be attributed to two independent effects: Inhibition of the PI3K/Akt/mTOR signaling pathway by one side, and AMPK activation by the other. In vivo experiments confirmed the synergistic effects of docetaxel and capsaicin in reducing the tumor growth of PC3 cells. Conclusion: Combination of docetaxel and capsaicin represents a therapeutically relevant approach for the treatment of Prostate Cancer.
Language	English
Publishing date	2019-03-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2091573-1
ISSN	1475-2867
ISSN	1475-2867
DOI	10.1186/s12935-019-0769-2
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Article ; Online: Capsaicin exerts synergistic antitumor effect with sorafenib in hepatocellular carcinoma cells through AMPK activation.

Bort, Alicia / Spínola, Elena / Rodríguez-Henche, Nieves / Díaz-Laviada, Inés

Oncotarget

2017 Volume 8, Issue 50, Page(s) 87684–87698

Abstract: In this study, we investigated the antitumoral effects of combined treatment using sorafenib and capsaicin in hepatocellular carcinoma (HCC) cells. Here we showed that the combination of the two drugs had a much stronger inhibitory effect on both HepG2 ... ...

Abstract	In this study, we investigated the antitumoral effects of combined treatment using sorafenib and capsaicin in hepatocellular carcinoma (HCC) cells. Here we showed that the combination of the two drugs had a much stronger inhibitory effect on both HepG2 and Huh-7 human HCC cells growth than either drug alone. The isobolograms demonstrated that the combinations investigated in this study produced a synergistic interaction. In the combination treatment using capsaicin and sorafenib, increased apoptosis, followed by the activation of caspase-9 and PARP, was observed. In addition, the present study demonstrated that sorafenib treatment induces activation of Akt, probably as a mechanism of resistance, whereas capsaicin inhibits Akt providing a possible pathway whereby capsaicin sensitizes to sorafenib in HCC cells. Moreover, capsaicin singly and the combination of capsaicin and sorafenib induce AMPK activation and Acetyl CoA carboxylase phosphorylation in HCC cells. Knocking down of AMPK by selective siRNA abrogates capsaicin-induced Akt inhibition, suggesting the involvement of AMPK in the antiproliferative effect.
Language	English
Publishing date	2017-10-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.21196
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Article: The potential antitumor effects of capsaicin.

Díaz-Laviada, Inés / Rodríguez-Henche, Nieves

Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques

2014 Volume 68, Page(s) 181–208

Abstract: Capsaicin, one of the major pungent ingredients found in red peppers, has been recently demonstrated to induce apoptosis in many types of malignant cell lines including colon adenocarcinoma, pancreatic cancer, hepatocellular carcinoma, prostate cancer, ... ...

Abstract	Capsaicin, one of the major pungent ingredients found in red peppers, has been recently demonstrated to induce apoptosis in many types of malignant cell lines including colon adenocarcinoma, pancreatic cancer, hepatocellular carcinoma, prostate cancer, breast cancer, and many others. The mechanism whereby capsaicin induces apoptosis in cancer cells is not completely elucidated but involves intracellular calcium increase, reactive oxygen species generation, disruption of mitochondrial membrane transition potential, and activation of transcription factors such as NFkappaB and STATS. Recently, a role for the AMP-dependent kinase (AMPK) and autophagy pathways in capsaicin-triggered cell death has been proposed. In addition, capsaicin shows antitumor activity in vivo by reducing the growth of many tumors induced in mice. In this chapter, we report the last advances performed in the antitumor activity of capsaicin and review the main signaling pathways involved.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Autophagy ; Capsaicin/chemistry ; Capsaicin/pharmacology ; Capsaicin/therapeutic use ; Humans ; Neoplasms/drug therapy ; TRPV Cation Channels/drug effects ; TRPV Cation Channels/physiology
Chemical Substances	Antineoplastic Agents ; TRPV Cation Channels ; TRPV1 receptor ; Capsaicin (S07O44R1ZM)
Language	English
Publishing date	2014-06-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	0071-786X
ISSN	0071-786X
DOI	10.1007/978-3-0348-0828-6_8
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Article ; Online: The red pepper's spicy ingredient capsaicin activates AMPK in HepG2 cells through CaMKKβ.

Bort, Alicia / Sánchez, Belén G / Spínola, Elena / Mateos-Gómez, Pedro A / Rodríguez-Henche, Nieves / Díaz-Laviada, Inés

PloS one

2019 Volume 14, Issue 1, Page(s) e0211420

Abstract: Capsaicin is a natural compound present in chili and red peppers and the responsible of their spicy flavor. It has recently provoked interest because of its antitumoral effects in many cell types although its action mechanism is not clearly understood. ... ...

Abstract	Capsaicin is a natural compound present in chili and red peppers and the responsible of their spicy flavor. It has recently provoked interest because of its antitumoral effects in many cell types although its action mechanism is not clearly understood. As metabolic dysregulation is one of the hallmarks of cancer cells and the key metabolic sensor in the AMP-activated kinase (AMPK), in this study we explored the ability of capsaicin to modulate AMPK activity. We found that capsaicin activated AMPK in HepG2 cells by increasing AMPK phosphorylation and its downstream target ACC. Mechanistically, we determined that capsaicin activated AMPK through the calcium/calmodulin-dependent protein kinase kinase β, CaMKKβ as either the CaMKK inhibitor STO-609 or CaMKK knock down with siRNA abrogated the activation of AMPK. Moreover, capsaicin decreased cell viability, inhibited Akt/mTOR pathway and increased reactive oxygen species (ROS) in HepG2 cells. AMPK activation was involved in the underpinning mechanism of capsaicin-induced cell death.
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Benzimidazoles/pharmacology ; Calcium/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Kinase/antagonists & inhibitors ; Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism ; Capsaicin/pharmacology ; Capsicum/chemistry ; Cell Survival ; Enzyme Activation ; Gene Expression Regulation, Enzymologic/drug effects ; Hep G2 Cells ; Humans ; Naphthalimides/pharmacology ; Phosphorylation ; Sensory System Agents/pharmacology ; Signal Transduction
Chemical Substances	Benzimidazoles ; Naphthalimides ; STO 609 ; Sensory System Agents ; CAMKK1 protein, human (EC 2.7.11.17) ; Calcium-Calmodulin-Dependent Protein Kinase Kinase (EC 2.7.11.17) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Capsaicin (S07O44R1ZM) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2019-01-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0211420
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Article ; Online: Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib.

Bort, Alicia / Sánchez, Belén G / Mateos-Gómez, Pedro A / Vara-Ciruelos, Diana / Rodríguez-Henche, Nieves / Díaz-Laviada, Inés

Molecular oncology

2019 Volume 13, Issue 5, Page(s) 1311–1331

Abstract: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem ... ...

Abstract	Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells (CSCs) that self-renew and often escape therapy. The key metabolic sensor AMP-activated kinase (AMPK) has recently been recognized as a tumour growth regulator. In this study, we aimed to elucidate the role of AMPK in the development of a stem cell phenotype in HCC cells. To this end, we enriched the CSC population in HCC cell lines that showed increased expression of drug resistance (ALDH1A1, ABCB1A) and stem cell (CD133, Nanog, Oct4, alpha fetoprotein) markers and demonstrated their stemness phenotype. These cells were refractory to sorafenib-induced cell death. We report that sorafenib-resistant cells had lower levels of total and phosphorylated AMPK as well as its downstream substrate, ACC, compared with the parental cells. Interestingly, AMPK knockdown with siRNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib-induced cell death. Conversely, the upregulation of AMPK, either by transfection or by pharmacological activation with A-769662, decreased the expression of ALDH1A1, ABCB1A, CD133, Nanog, Oct4, and alpha fetoprotein, and restored sensitivity to sorafenib. Analysis of the underlying mechanism points to hypoxia-inducible factor HIF-1α as a regulator of stemness. In vivo studies in a xenograft mouse model demonstrated that stem-like cells have greater tumourigenic capacity. AMPK activation reduced xenograft tumour growth and decreased the expression of stem cell markers. Taken together, these results indicate that AMPK may serve as a novel target to overcome chemoresistance in HCC.
MeSH term(s)	AMP-Activated Protein Kinases/antagonists & inhibitors ; AMP-Activated Protein Kinases/metabolism ; Animals ; Biomarkers, Tumor/antagonists & inhibitors ; Biomarkers, Tumor/metabolism ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/enzymology ; Carcinoma, Hepatocellular/pathology ; Drug Resistance, Neoplasm/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/enzymology ; Liver Neoplasms/pathology ; Mice ; Mice, Nude ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/metabolism ; Neoplastic Stem Cells/enzymology ; Neoplastic Stem Cells/pathology ; Pyrones/pharmacology ; Sorafenib/pharmacology ; Thiophenes/pharmacology ; Time Factors ; Xenograft Model Antitumor Assays
Chemical Substances	Biomarkers, Tumor ; Neoplasm Proteins ; Pyrones ; Thiophenes ; Sorafenib (9ZOQ3TZI87) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; 4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile (P68477CD2C)
Language	English
Publishing date	2019-04-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.12488
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Article ; Online: The pepper's natural ingredient capsaicin induces autophagy blockage in prostate cancer cells.

Ramos-Torres, Ágata / Bort, Alicia / Morell, Cecilia / Rodríguez-Henche, Nieves / Díaz-Laviada, Inés

Oncotarget

2016 Volume 7, Issue 2, Page(s) 1569–1583

Abstract: Capsaicin, the pungent ingredient of red hot chili peepers, has been shown to have anti-cancer activities in several cancer cells, including prostate cancer. Several molecular mechanisms have been proposed on its chemopreventive action, including ... ...

Abstract	Capsaicin, the pungent ingredient of red hot chili peepers, has been shown to have anti-cancer activities in several cancer cells, including prostate cancer. Several molecular mechanisms have been proposed on its chemopreventive action, including ceramide accumulation, endoplasmic reticulum stress induction and NFκB inhibition. However, the precise mechanisms by which capsaicin exerts its anti-proliferative effect in prostate cancer cells remain questionable. Herein, we have tested the involvement of autophagy on the capsaicin mechanism of action on prostate cancer LNCaP and PC-3 cells.The results showed that capsaicin induced prostate cancer cell death in a time- and concentration-dependent manner, increased the levels of microtubule-associated protein light chain 3-II (LC3-II, a marker of autophagy) and the accumulation of the cargo protein p62 suggesting an autophagy blockage. Moreover, confocal microscopy revealed that capsaicin treatment increased lysosomes which co-localized with LC3 positive vesicles in a similar extent to that produced by the lysosomal protease inhibitors E64 and pepstatin pointing to an autophagolysosomes breakdown inhibition. Furthermore, we found that capsaicin triggered ROS generation in cells, while the levels of ROS decreased with N-acetyl-cysteine (NAC), a ROS scavenger. Co-treatment of cells with NAC and capsaicin abrogated the effects of capsaicin on autophagy and cell death. Normal prostate PNT2 and RWPE-1 cells were more resistant to capsaicin-induced cytotoxicity and did not accumulate p62 protein.Taken together, these results suggest that ROS-mediated capsaicin-induced autophagy blockage contributes to antiproliferation in prostate cancer cells, which provides new insights into the anticancer molecular mechanism of capsaicin.
MeSH term(s)	Antineoplastic Agents, Phytogenic/isolation & purification ; Antineoplastic Agents, Phytogenic/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Autophagy/drug effects ; Capsaicin/isolation & purification ; Capsaicin/pharmacology ; Capsicum/chemistry ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Humans ; Lysosomes/drug effects ; Lysosomes/metabolism ; Male ; Microtubule-Associated Proteins/metabolism ; Phosphatidylinositol 3-Kinase/metabolism ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; Time Factors
Chemical Substances	Antineoplastic Agents, Phytogenic ; Antioxidants ; MAP1LC3A protein, human ; Microtubule-Associated Proteins ; Reactive Oxygen Species ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Capsaicin (S07O44R1ZM)
Language	English
Publishing date	2016-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.6415
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Article ; Online: Up-Regulated Expression of LAMP2 and Autophagy Activity during Neuroendocrine Differentiation of Prostate Cancer LNCaP Cells.

Morell, Cecilia / Bort, Alicia / Vara-Ciruelos, Diana / Ramos-Torres, Ágata / Altamirano-Dimas, Manuel / Díaz-Laviada, Inés / Rodríguez-Henche, Nieves

PloS one

2016 Volume 11, Issue 9, Page(s) e0162977

Abstract: Neuroendocrine (NE) prostate cancer (PCa) is a highly aggressive subtype of prostate cancer associated with resistance to androgen ablation therapy. In this study, we used LNCaP prostate cancer cells cultured in a serum-free medium for 6 days as a NE ... ...

Abstract	Neuroendocrine (NE) prostate cancer (PCa) is a highly aggressive subtype of prostate cancer associated with resistance to androgen ablation therapy. In this study, we used LNCaP prostate cancer cells cultured in a serum-free medium for 6 days as a NE model of prostate cancer. Serum deprivation increased the expression of NE markers such as neuron-specific enolase (NSE) and βIII tubulin (βIII tub) and decreased the expression of the androgen receptor protein in LNCaP cells. Using cDNA microarrays, we compared gene expression profiles of NE cells and non-differentiated LNCaP cells. We identified up-regulation of 155 genes, among them LAMP2, a lysosomal membrane protein involved in lysosomal stability and autophagy. We then confirmed up-regulation of LAMP2 in NE cells by qRT-PCR, Western blot and confocal microscopy assays, showing that mRNA up-regulation correlated with increased levels of LAMP2 protein. Subsequently, we determined autophagy activity in NE cells by assessing the protein levels of SQSTM/p62 and LC3 by Western blot and LC3 and Atg5 mRNAs content by qRT-PCR. The decreased levels of SQSTM/p62 was accompanied by an enhanced expression of LC3 and ATG5, suggesting activation of autophagy in NE cells. Blockage of autophagy with 1μM AKT inhibitor IV, or by silencing Beclin 1 and Atg5, prevented NE cell differentiation, as revealed by decreased levels of the NE markers. In addition, AKT inhibitor IV as well as Beclin1 and Atg5 kwockdown attenuated LAMP2 expression in NE cells. On the other hand, LAMP2 knockdown by siRNA led to a marked blockage of autophagy, prevention of NE differentiation and decrease of cell survival. Taken together, these results suggest that LAMP2 overexpression assists NE differentiation of LNCaP cells induced by serum deprivation and facilitates autophagy activity in order to attain the NE phenotype and cell survival. LAMP2 could thus be a potential biomarker and potential target for NE prostate cancer.
MeSH term(s)	Autophagy/physiology ; Blotting, Western ; Cell Line, Tumor ; Cell Transformation, Neoplastic/metabolism ; Gene Expression Regulation, Neoplastic/physiology ; Humans ; Lysosomal-Associated Membrane Protein 2/metabolism ; Lysosomal-Associated Membrane Protein 2/physiology ; Male ; Microscopy, Confocal ; Oligonucleotide Array Sequence Analysis ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/physiopathology ; Real-Time Polymerase Chain Reaction ; Transcriptome ; Up-Regulation
Chemical Substances	LAMP2 protein, human ; Lysosomal-Associated Membrane Protein 2
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0162977
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Article ; Online: Identification of a novel 2-oxindole fluorinated derivative as in vivo antitumor agent for prostate cancer acting via AMPK activation.

Bort, Alicia / Quesada, Sergio / Ramos-Torres, Ágata / Gargantilla, Marta / Priego, Eva María / Raynal, Sophie / Lepifre, Franck / Gasalla, Jose M / Rodriguez-Henche, Nieves / Castro, Ana / Díaz-Laviada, Inés

Scientific reports

2018 Volume 8, Issue 1, Page(s) 4370

Abstract: The key metabolic sensor adenosine monophosphate-dependent kinase (AMPK) has emerged as a promising therapeutic target for cancer prevention and treatment. Besides its role in energy homeostasis, AMPK blocks cell cycle, regulates autophagy and suppresses ...

Abstract	The key metabolic sensor adenosine monophosphate-dependent kinase (AMPK) has emerged as a promising therapeutic target for cancer prevention and treatment. Besides its role in energy homeostasis, AMPK blocks cell cycle, regulates autophagy and suppresses the anabolic processes required for rapid cell growth. AMPK is especially relevant in prostate cancer in which activation of lipogenic pathways correlate with tumor progression and aggressiveness. This study reports the discovery of a new series of 2-oxindole derivatives whose AMPK modulatory ability, as well as the antitumoral profile in prostate cancer cells, was evaluated. One of the assayed compounds, compound 8c, notably activated AMPK in cultured PC-3, DU145 and LNCaP prostate cancer cells. Likewise, compound 8c caused PC-3, DU145 and LNCaP cells viability inhibition. Selective knocking down of α1 or α2 isoforms as well as in vitro assays using human recombinant α1β1γ1 or α2β1γ1 AMPK isoforms revealed that compound 8c exhibit preference for AMPKα1. Consistent with efficacy at the cellular level, compound 8c was potent in suppressing the growth of PC-3 xenograft tumors. In conclusion, our results show that a new 2-oxindole fluorinated derivative exerts potent in vivo antitumor actions against prostate cancer cells, indicating a promising clinical therapeutic strategy for the treatment of androgen-independent prostate cancer.
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Halogenation ; Humans ; Male ; Oxindoles/chemical synthesis ; Oxindoles/chemistry ; Oxindoles/pharmacology ; Phosphorylation ; Prostatic Neoplasms/drug therapy ; Protein Isoforms
Chemical Substances	Antineoplastic Agents ; Oxindoles ; Protein Isoforms ; 2-oxindole (0S9338U62H) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2018-03-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-22690-2
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Article ; Online: Novel cancer chemotherapy hits by molecular topology: dual Akt and Beta-catenin inhibitors.

Zanni, Riccardo / Galvez-Llompart, Maria / Morell, Cecilia / Rodríguez-Henche, Nieves / Díaz-Laviada, Inés / Recio-Iglesias, Maria Carmen / Garcia-Domenech, Ramon / Galvez, Jorge

PloS one

2015 Volume 10, Issue 4, Page(s) e0124244

Abstract: Background and purpose: Colorectal and prostate cancers are two of the most common types and cause of a high rate of deaths worldwide. Therefore, any strategy to stop or at least slacken the development and progression of malignant cells is an important ...

Abstract	Background and purpose: Colorectal and prostate cancers are two of the most common types and cause of a high rate of deaths worldwide. Therefore, any strategy to stop or at least slacken the development and progression of malignant cells is an important therapeutic choice. The aim of the present work is the identification of novel cancer chemotherapy agents. Nowadays, many different drug discovery approaches are available, but this paper focuses on Molecular Topology, which has already demonstrated its extraordinary efficacy in this field, particularly in the identification of new hit and lead compounds against cancer. This methodology uses the graph theoretical formalism to numerically characterize molecular structures through the so called topological indices. Once obtained a specific framework, it allows the construction of complex mathematical models that can be used to predict physical, chemical or biological properties of compounds. In addition, Molecular Topology is highly efficient in selecting and designing new hit and lead drugs. According to the aforementioned, Molecular Topology has been applied here for the construction of specific Akt/mTOR and β-catenin inhibition mathematical models in order to identify and select novel antitumor agents. Experimental approach: Based on the results obtained by the selected mathematical models, six novel potential inhibitors of the Akt/mTOR and β-catenin pathways were identified. These compounds were then tested in vitro to confirm their biological activity. Conclusion and implications: Five of the selected compounds, CAS n° 256378-54-8 (Inhibitor n°1), 663203-38-1 (Inhibitor n°2), 247079-73-8 (Inhibitor n°3), 689769-86-6 (Inhibitor n°4) and 431925-096 (Inhibitor n°6) gave positive responses and resulted to be active for Akt/mTOR and/or β-catenin inhibition. This study confirms once again the Molecular Topology's reliability and efficacy to find out novel drugs in the field of cancer.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Biological Products/chemistry ; Biological Products/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Discovery ; Humans ; Molecular Structure ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/chemistry ; Proto-Oncogene Proteins c-akt/metabolism ; Quantitative Structure-Activity Relationship ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/chemistry ; TOR Serine-Threonine Kinases/metabolism ; beta Catenin/antagonists & inhibitors ; beta Catenin/chemistry ; beta Catenin/metabolism
Chemical Substances	Antineoplastic Agents ; Biological Products ; Protein Kinase Inhibitors ; beta Catenin ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2015-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0124244
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Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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Inter-library loan at ZB MED

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Order via subito

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Order via subito

Inter-library loan at ZB MED