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1.
Eur J Med Chem ; 177: 171-187, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132532

RESUMO

Nur77, an orphan member of the nuclear receptor superfamily, plays an important role in the regulation of inflammatory processes. Our previous work found that celastrol, a pentacyclic triterpene, bound to Nur77 to inhibit inflammation in a Nur77-dependent manner. Celastrol binding to Nur77 promotes Nur77 translocation from nucleus to cytoplasm, resulting in clearance of inflamed mitochondria and then alleviation of inflammation. Here, we report the design, synthesis, SAR study and biological evaluation of a series of celastrol analogs. A total of 24 celastrol derivatives were made. Compound 3a with a Kd of 0.87 µM was found to be less toxic than celastrol and could be a hit molecule for further optimization.


Assuntos
Anti-Inflamatórios/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/antagonistas & inibidores , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/toxicidade , Sítios de Ligação , Desenho de Drogas , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/química , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteína Sequestossoma-1/metabolismo , Relação Estrutura-Atividade , Fator 2 Associado a Receptor de TNF/metabolismo , Triterpenos/síntese química , Triterpenos/metabolismo , Triterpenos/toxicidade , Peixe-Zebra
2.
Nat Commun ; 10(1): 1463, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931933

RESUMO

Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXRα is abnormally cleaved in tumor cells and tissues, producing a truncated RXRα (tRXRα). Here, we show that transgenic expression of tRXRα in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXRα is primarily dependent on its expression in myeloid cells, which results in interleukin-6 (IL-6) induction and STAT3 activation. Mechanistic studies reveal an extensive interaction between tRXRα and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-κB inflammatory pathway. K-80003, a tRXRα modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRα-mediated colorectal tumor by inhibiting the NF-κB-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRα action and identify a promising tRXRα ligand for treating CAC.


Assuntos
Carcinogênese/genética , Colite/genética , Neoplasias Colorretais/genética , Interleucina-6/imunologia , Receptor X Retinoide alfa/genética , Fator de Transcrição STAT3/imunologia , Animais , Carcinogênese/imunologia , Colite/imunologia , Colite Ulcerativa/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/metabolismo , Neoplasias Colorretais/imunologia , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Células HCT116 , Humanos , Inflamação , Macrófagos/imunologia , Camundongos , NF-kappa B/imunologia , Receptor X Retinoide alfa/imunologia , Transdução de Sinais , Sulindaco/análogos & derivados , Sulindaco/farmacologia , Fator 6 Associado a Receptor de TNF/imunologia
3.
Mar Drugs ; 17(3)2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893778

RESUMO

Five new ergostanes, penicisteroids D-H (1-5), were isolated from the liquid culture of the deep-sea-derived fungus Penicillium granulatum MCCC 3A00475, along with 27 known compounds. The structures of the new steroids were established mainly on the basis of extensive analysis of 1D and 2D NMR as well as HRESIMS data. Moreover, the absolute configurations of 1 were confirmed unambiguously by the single-crystal X-ray crystallography. Compounds 2 and 4⁻7 showed moderate antiproliferative effects selectively against 12 different cancer cell lines with IC50 values of around 5 µM. Compounds 2 and 6, potent RXRα binders with Kd values of 13.8 and 12.9 µM, respectively, could induce apoptosis by a Retinoid X Receptor (RXR)-α-dependent mechanism by regulating RXRα transcriptional expression and promoting the poly-ADP-ribose polymerase (PARP) cleavage. Moreover, they could inhibit proliferation by cell cycle arrest at the G0/G1 phase.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Organismos Aquáticos/química , Ergosterol/farmacologia , Penicillium/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Ergosterol/análogos & derivados , Ergosterol/química , Ergosterol/isolamento & purificação , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Sedimentos Geológicos/microbiologia , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Receptor X Retinoide alfa/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Mol Cancer Ther ; 18(5): 886-899, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30926635

RESUMO

Nur77 (also called TR3 or NGFI-B), an orphan member of the nuclear receptor superfamily, induces apoptosis by translocating to mitochondria where it interacts with Bcl-2 to convert Bcl-2 from an antiapoptotic to a pro-apoptotic molecule. Nur77 posttranslational modification such as phosphorylation has been shown to induce Nur77 translocation from the nucleus to mitochondria. However, small molecules that can bind directly to Nur77 to trigger its mitochondrial localization and Bcl-2 interaction remain to be explored. Here, we report our identification and characterization of DIM-C-pPhCF3 +MeSO3 - (BI1071), an oxidized product derived from indole-3-carbinol metabolite, as a modulator of the Nur77-Bcl-2 apoptotic pathway. BI1071 binds Nur77 with high affinity, promotes Nur77 mitochondrial targeting and interaction with Bcl-2, and effectively induces apoptosis of cancer cells in a Nur77- and Bcl-2-dependent manner. Studies with animal model showed that BI1071 potently inhibited the growth of tumor cells in animals through its induction of apoptosis. Our results identify BI1071 as a novel Nur77-binding modulator of the Nur77-Bcl-2 apoptotic pathway, which may serve as a promising lead for treating cancers with overexpression of Bcl-2.

5.
Bioorg Med Chem Lett ; 29(5): 707-712, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30670347

RESUMO

The orphan nuclear receptor Nur77 (also known as TR3 or nerve growth factor-induced clone B NGFI-B) functions as a nuclear transcription factor in the regulation of target gene expression and plays a critical role in the regulation of differentiation, proliferation, apoptosis, and survival of many different cell types. Recent studies demonstrate that Nur77 also involves many important physiological and pathological processes including cancer, inflammation and immunity, cardiovascular diseases, and bone diseases. Our previous studies showed that cardiac glycosides could induce the expression of Nur77 protein and its translocation from the nucleus to the cytoplasm and subsequent targeting to mitochondria, leading to apoptosis of cancer cells. In order to probe the Nur77 protein inducting pathway, we designed and synthesized a series of novel biotinylated cardiac glycosides from ß-Antiarin and α-Antiarin, two typical cardiac glycosides from the plant of Antiaris toxicaria. The induction of Nur77 protein expression of these biotinylated cardiac glycosides and their inhibitory effects on NIH-H460 cancer cell proliferation were evaluated. Results displayed that some biotinylated cardiac glycosides could significantly induce the expression of Nur77 protein comparable with their parent compounds ß-Antiarin and α-Antiarin. Also, their streptavidin binding activities were evaluated. Among them, biotinylated cardiac glycosides P4b and P5a exhibited significant effect on the induction of Nur77 expression along with high binding capacity with streptavidin, suggesting that they can be used as probes for probing Nur77 protein inducting pathway.

7.
J Cell Mol Med ; 2018 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-30370662

RESUMO

Matriptase is an epithelia-specific membrane-anchored serine protease, and its dysregulation is highly related to the progression of a variety of cancers. Hepatocyte growth factor activator inhibitor-1 (HAI-1) inhibits matriptase activity through forming complex with activated matriptase. The balance of matriptase activation and matriptase/HAI-1 complex formation determines the intensity and duration of matriptase activity. 3-Cl-AHPC, 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid, is an adamantly substituted retinoid-related molecule and a ligand of retinoic acid receptor γ (RARγ). 3-Cl-AHPC is of strong anti-cancer effect but with elusive mechanisms. In our current study, we show that 3-Cl-AHPC time- and dose- dependently induces matriptase/HAI-1 complex formation, leading to the suppression of activated matriptase in cancer cells and tissues. Furthermore, 3-Cl-AHPC promotes matriptase shedding but without increasing the activity of shed matriptase. Moreover, 3-Cl-AHPC inhibits matriptase-mediated cleavage of pro-HGF through matriptase/HAI-1 complex induction, resulting in the suppression of pro-HGF-stimulated signalling and cell scattering. Although 3-Cl-AHPC binds to RARγ, its induction of matriptase/HAI-1 complex is not RARγ dependent. Together, our data demonstrates that 3-Cl-AHPC down-regulates matriptase activity through induction of matriptase/HAI-1 complex formation in a RARγ-independent manner, providing a mechanism of 3-Cl-AHPC anti-cancer activity and a new strategy to inhibit abnormal matriptase activity via matriptase/HAI-1 complex induction using small molecules.

8.
Chem Commun (Camb) ; 54(91): 12871-12874, 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30376017

RESUMO

Celastrol is one of the most studied natural products. Our studies show for the first time that celastrol can bind to its target protein via specific noncovalent interactions that position celastrol next to the thiol group of the reactive cysteine for reversible covalent bond formation. Such specific noncovalent interactions confer celastrol binding specificity and demonstrate the feasibility of improving the efficacy and selectivity of celastrol for therapeutic applications.

9.
Mol Cell Oncol ; 5(3): e1327005, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30250883

RESUMO

Selective clearance of damaged mitochondria can reverse pathological status in chronic inflammatory diseases. We recently identified a critical role of nuclear receptor Nur77 and celastrol in priming inflamed mitochondria for autophagy through its mitochondrial targeting and interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2) and the autophagic adaptor p62/SQSTM1.

10.
Mol Pharm ; 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29995422

RESUMO

Bexarotene, an agonist of retinoid X receptor alpha (RXRα), has been shown to increase the expression of apoE, ABCA1 and ABCG1 by activating RXR/LXR and RXR/PPAR heterodimers, resulting in amyloid ß (Aß)-protein clearance in the brain of an Alzheimer's Disease (AD) mouse model and reversal of mouse cognitive deficits. Nitrostyrene derivative Z-10 is the first identified nitro-ligand of RXRα. We hypothesized that Z-10 and its derivatives have the similar effect as bexarotene. A series of Z-10 derivatives were synthesized by introducing methyl, hydroxyl, and methoxy groups in 2- or 4- position of naphthalene ring, respectively. Our reporter gene assays showed that the derivatives with substituted groups of methyl and methoxy in position 2 were more potent to activate Gal4-DBD/RXRα-LBD and RXRα homodimer as well as RXRα heterodimers than the corresponding 4-substituted derivatives. The derivatives with hydroxyl substitution in either 2- or 4- position failed to activate RXRα. Consistently, the derivatives with stronger potency of RXRα activation had higher RXRα binding affinity. Z-10 and its 2-ethyoxyl substituted derivative Z-36 reduced Aß plaques in both hippocampus and cortex of AD mouse model significantly, of which Z-36 had stronger efficacy. This may due to the stronger ability of Z-36 than Z-10 in activating RXR/LXR and RXR/PPAR heterodimers and inducing ABCA1 and ABCG1 expressions. Thus, the 2- rather than 4- position was the better site for Z-10 modification as to RXRα transactivation, and Z-36 is an optimized derivative of Z-10 as to reducing Aß plaques in AD mouse model.

11.
Oncotarget ; 9(38): 25057-25074, 2018 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-29861853

RESUMO

Di(1H-indol-3-yl)(4-trifluoromethylphenyl)methane (DIM-Ph-4-CF3) is an analog of orphan nuclear receptor 4A1 (NR4A1) ligand cytosporone B. We have synthesized several oxidation products of DIM-Ph-4-CF3, focusing on analogs with electron-withdrawing or donating groups at their phenyl ring 4-positions, and examined their anti-cancer activity and mechanism-of-action. Mesylates (DIM-Ph-4-X+ OMs-s) having CF3, CO2Me and Cl groups were more effective inhibitors of cancer cell viability than their precursors. 19F NMR spectroscopy and differential scanning calorimetry strongly indicated interactions of DIM-Ph-4-CF3+ OMs- with the NR4A1 ligand binding domain, and compound-induced apoptosis of prostate cancer cells was dependent on NR4A1. DIM-Ph-4-CF3+ OMs- showed robust inhibition of LNCaP prostate cancer xenografts with no apparent toxicity. In vitro and in vivo, DIM-Ph-4-CF3+ OMs- activated proapoptotic unfolded protein response (UPR) signaling in prostate cancer cells. Independently of DIM-Ph-4-CF3+ OMs-, the bulk of NR4A1 localized to the cytoplasm in various cancer cell lines, suggesting a cytoplasmic mechanism-of-action of DIM-Ph-4-CF3+ OMs- in UPR induction and cell death. In summary, the data suggest that oxidized analogs of DIM-Ph-4-CF3 possess potent and safe anti-cancer activity which is mediated through UPR signaling downstream of NR4A1 binding.

12.
Oncotarget ; 9(40): 26072-26085, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29899843

RESUMO

Resistance to chemotherapy is a major cause of treatment failure and poor overall survival in patients with lung cancer. Identification of molecular targets present in resistant cancer cells is essential for addressing therapeutic resistance and prolonging lung cancer patient survival. Members of the B-cell lymphoma 2 (Bcl-2) family of proteins are associated with chemotherapeutic resistance. In this study, we found that pro-survival protein Bcl-2 is upregulated in paclitaxel resistant cells, potentially contributing to chemotherapy resistance. To exploit the increase in Bcl-2 expression for targeting therapy resistance, we investigated the effects of a peptide derived from the nuclear receptor Nur77 that converts Bcl-2 from an anti-apoptotic protein to a pro-apoptotic protein. The Nur77 derived peptide preferentially induced apoptosis in paclitaxel-resistant cancer cells with high expression of Bcl-2. This peptide also induced apoptosis of multidrug resistant H69AR lung cancer cells that express Bcl-2 and inhibited their growth in 3D spheroids. The Nur77 peptide strongly suppressed the growth of paclitaxel-resistant lung cancer cells in a zebrafish xenograft tumor model. Taken together, our data supports a new strategy for treating lung cancers that acquire resistance to chemotherapy through overexpression of Bcl-2.

13.
Eur J Med Chem ; 145: 252-262, 2018 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-29329000

RESUMO

Cardiac glycosides exhibit significant anticancer effects and the glycosyl substitution at C3 position of digoxigenin is pivotal for their biological activity. In order to study the structure-activity relationship (SAR) of cardiac glycosides toward cancers and explore more potent anticancer agents, a series of C3-O-neoglycosides and C3-MeON-neoglycosides of digoxigenin were synthesized by the Koenigs-Knorr and neoglycosylation method, respectively. In addition, digoxigenin bisdigitoxoside and monodigitoxoside were prepared from digoxin by sodium periodate (NaIO4) oxidation and 6-aminocaproic acid hydrolysis. The SAR analysis revealed that C3-O-neoglycosides of digoxigenin exhibited stronger cytotoxicity and induction of Nur77 expression of tumor cells than C3-MeON-neoglycosides. Also, 3ß-O-glycosides exhibited stronger anticancer effects than 3α-O-glycosides. Among them, 3ß-O-(ß-l-fucopyranosyl)-digoxigenin (3i) showed the highest activity on induction of Nur77 expression and translocation from the nucleus to cytoplasm, leading to cancer cell apoptosis.


Assuntos
Antineoplásicos/farmacologia , Digoxigenina/farmacologia , Glicosídeos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Digoxigenina/síntese química , Digoxigenina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/síntese química , Glicosídeos/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Oncotarget ; 8(41): 69731-69745, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-29050237

RESUMO

Orphan nuclear receptor Nur77 promotes apoptosis by targeting mitochondria through interaction with Bcl-2, an event that converts Bcl-2 from a survival to killer. However, how the Nur77-Bcl-2 apoptotic pathway is regulated remains largely unknown. In this study, we examined the regulation of the Nur77-Bcl-2 pathway by CCE9, a xanthone compound. Our results demonstrated that the apoptotic effect of CCE9 depended on its induction of Nur77 expression, cytoplasmic localization, and mitochondrial targeting. The activation of the Nur77-Bcl-2 pathway by CCE9 was associated with its activation of p38α MAPK. Inhibition of p38α MAPK activation by knocking down or knocking out p38α MAPK impaired the effect of CCE9 on inducing apoptosis and the expression and cytoplasmic localization of Nur77. In addition, CCE9 activation of p38α MAPK resulted in Bcl-2 phosphorylation and Bcl-2 interaction with Nur77, whereas inhibition of p38α MAPK activation or expression suppressed the interaction. Moreover, mutating Ser87 and Thr56 in the loop of Bcl-2, which are known to be phosphorylated by p38α MAPK, impaired the ability Bcl-2 to interact with Nur77. Together, our results reveal a profound role of p38α MAPK in regulating the Nur77-Bcl-2 apoptotic pathway through its modulation of Nur77 expression, Bcl-2 phosphorylation, and their interaction.

15.
Nat Commun ; 8: 16066, 2017 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-28714476

RESUMO

Retinoid X receptor-alpha (RXRα) binds to DNA either as homodimers or heterodimers, but it also forms homotetramers whose function is poorly defined. We previously discovered that an N-terminally-cleaved form of RXRα (tRXRα), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85α subunit of PI3K and that K-80003, an anti-cancer agent, inhibits this process. Here, we report through crystallographic and biochemical studies that K-80003 binds to and stabilizes tRXRα tetramers via a 'three-pronged' combination of canonical and non-canonical mechanisms. K-80003 binding has no effect on tetramerization of RXRα, owing to the head-tail interaction that is absent in tRXRα. We also identify an LxxLL motif in p85α, which binds to the coactivator-binding groove on tRXRα and dissociates from tRXRα upon tRXRα tetramerization. These results identify conformational selection as the mechanism for inhibiting the nongenomic action of tRXRα and provide molecular insights into the development of RXRα cancer therapeutics.

16.
Bioorg Med Chem Lett ; 27(15): 3359-3364, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28633895

RESUMO

Cardiac glycosides show anticancer activities and their deoxy-sugar chains are vital for their anticancer effects. In order to study the structure-activity relationship (SAR) of cardiac glycosides toward cancers and get more potent anticancer agents, a series of MeON-neoglycosides of digoxigenin was synthesized and evaluated. First, ten 6-deoxy- and 2,6-dideoxy-d-glucopyranosyl donors were synthesized starting from methyl α-d-glucopyranoside and 2-deoxy-d-glucose. Meanwhile, the digoxigenin was obtained by acidic hydrolysis of commercially available digoxin as glycosyl acceptor. Then, a 22-member MeON-neoglycoside library of digoxigenin was successfully synthesized by neoglycosylation method. Finally, the induction of Nur77 expression and its translocation from the nucleus to cytoplasm together with cytotoxicity of these MeON-neoglycosides were evaluated. The SAR analysis revealed that C3 glycosylation is required for their induction of Nur77 expression. Moreover, some MeON-neoglycosides (2b and 8b) could significant induce the expression of Nur77 and its translocation from the nucleus to cytoplasm. However, these compounds showed no inhibitory effects on the proliferation of cancer cells, suggesting that they may not induce apoptosis of NIH-H460 cancer cells and their underlying potential and application toward cancer cells deserves future study.


Assuntos
Antineoplásicos/farmacologia , Digoxigenina/farmacologia , Glucose/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Digoxigenina/síntese química , Digoxigenina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glucose/análogos & derivados , Glucose/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
17.
Mol Cell ; 66(1): 141-153.e6, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28388439

RESUMO

Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a critical intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Mitocôndrias Hepáticas/efeitos dos fármacos , Degradação Mitocondrial/efeitos dos fármacos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Triterpenos/farmacologia , Ubiquitinação/efeitos dos fármacos , Transporte Ativo do Núcleo Celular , Animais , Anti-Inflamatórios/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Feminino , Genótipo , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/deficiência , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Fenótipo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Interferência de RNA , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator 2 Associado a Receptor de TNF/genética , Transfecção , Triterpenos/metabolismo
18.
Sci Rep ; 7(1): 348, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28336971

RESUMO

We recently demonstrated that retinoic acid receptor-γ (RARγ) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RARγ is mainly attributed to its physiological interaction with p85α regulatory subunit of PI3K leading to constitutive activation of AKT. Here we report RARγ as a negative regulator of p53 signaling and thus extend the oncogenic potential of RARγ to a new role in controlling the balance between AKT and p53. A natural flavonoid acacetin is then identified to be capable of modulating RARγ-dependent AKT-p53 network. It specifically binds to RARγ and inhibits all-trans retinoic acid (atRA) stimulation of RARγ transactivation. However, the anticancer action of acacetin is independent on its modulation of RARγ-driven transcriptional activity. Acacetin induces cancer cell apoptosis through antagonizing the non-genomic effect of RARγ on AKT and p53. When bound to RARγ, acacetin prevents RARγ from its activation of AKT followed by recovery of the normal p53 signaling. Given the implication of AKT-p53 dysregulation in most HCC, targeting the non-genomic signaling of RARγ that switches AKT-p53 from a pro-survival to a pro-apoptotic program in cancer cells should be a promising strategy for developing novel anti-HCC drugs.


Assuntos
Anticarcinógenos/administração & dosagem , Carcinoma Hepatocelular/metabolismo , Flavonas/administração & dosagem , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/metabolismo , Receptores do Ácido Retinoico/metabolismo , Animais , Apoptose , Genes p53 , Células HEK293 , Humanos , Camundongos Endogâmicos BALB C , Oncogenes , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Proteína X Associada a bcl-2/metabolismo
19.
Oncotarget ; 8(7): 12311-12322, 2017 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-28129653

RESUMO

The major oncogenic driver of acute promyelocytic leukemia (APL) is the fusion protein PML-RARα originated from the chromosomal translocation t(15;17). All-trans retinoic acid (ATRA) and arsenic trioxide cure most patients by directly targeting PML-RARα. However, major issues including the resistance of ATRA and arsenic therapy still remain in APL clinical management. Here we showed that compound Z-10, a nitro-ligand of retinoid X receptor α (RXRα), strongly promoted the cAMP-independent apoptosis of both ATRA- sensitive and resistant NB4 cells via the induction of caspase-mediated PML-RARα degradation. RXRα was vital for the stability of both PML-RARα and RARα likely through the interactions. The binding of Z-10 to RXRα dramatically inhibited the interaction of RXRα with PML-RARα but not with RARα, leading to Z-10's selective induction of PML-RARα but not RARα degradation. Z-36 and Z-38, two derivatives of Z-10, had improved potency of inducing PML-RARα reduction and NB4 cell apoptosis. Hence, RXRα ligand Z-10 and its derivatives could target both ATRA- sensitive and resistant APL cells through their distinct acting mechanism, and are potential drug leads for APL treatment.


Assuntos
Apoptose/efeitos dos fármacos , Naftalenos/farmacologia , Nitrocompostos/farmacologia , Proteínas de Fusão Oncogênica/metabolismo , Receptor X Retinoide alfa/metabolismo , Estirenos/farmacologia , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Trióxido de Arsênio , Arsenicais/farmacologia , Western Blotting , Células COS , Caspases/metabolismo , Linhagem Celular Tumoral , Cercopithecus aethiops , AMP Cíclico/metabolismo , Citometria de Fluxo , Células HEK293 , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Ligantes , Naftalenos/metabolismo , Nitrocompostos/metabolismo , Óxidos/farmacologia , Ligação Proteica , Proteólise/efeitos dos fármacos , Estirenos/metabolismo , Tretinoína/farmacologia
20.
Curr Top Med Chem ; 17(6): 663-675, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27320331

RESUMO

Retinoid X receptors (RXRs) occupy a central position within the nuclear receptor superfamily. They not only function as important transcriptional factors but also exhibit diverse nongenomic biological activities. The pleiotropic actions of RXRs under both physiological and pathophysiological conditions confer RXRs important drug targets for the treatment of cancer, and metabolic and neurodegenerative diseases. RXR modulators have been studied for the purpose of developing both drug molecules and chemical tools for biological investigation of RXR. Development of RXR modulators has focused on small molecules targeting the canonical ligand-binding pocket. However, accumulating results have demonstrated that there are other binding mechanisms by which small molecules interact with RXR to act as RXR modulators. This review discusses the recent development in the design and discovery of RXR modulators with a focus on those targeting novel binding sites on RXR.


Assuntos
Desenho de Drogas , Descoberta de Drogas , Receptores X Retinoide/química , Animais , Sítios de Ligação , Humanos , Ligantes , Receptores X Retinoide/metabolismo
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