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1.
Sci Rep ; 12(1): 3115, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35210493

RESUMO

Nuclear receptors (NR) are ligand-modulated transcription factors that regulate multiple cell functions and thus represent excellent drug targets. However, due to a considerable NR structural homology, NR ligands often interact with multiple receptors. Here, we describe a multiplex reporter assay (the FACTORIAL NR) that enables parallel assessment of NR ligand activity across all 48 human NRs. The assay comprises one-hybrid GAL4-NR reporter modules transiently transfected into test cells. To evaluate the reporter activity, we assessed their RNA transcripts. We used a homogeneous RNA detection approach that afforded equal detection efficacy and permitted the multiplex detection in a single-well format. For validation, we examined a panel of selective NR ligands and polypharmacological agonists and antagonists of the progestin, estrogen, PPAR, ERR, and ROR receptors. The assay produced highly reproducible NR activity profiles (r > 0.96) permitting quantitative assessment of individual NR responses. The inferred EC50 values agreed with the published data. The assay showed excellent quality ( = 0.73) and low variability ( = 7.2%). Furthermore, the assay permitted distinguishing direct and non-direct NR responses to ligands. Therefore, the FACTORIAL NR enables comprehensive evaluation of NR ligand polypharmacology.


Assuntos
Ligantes , Polifarmacologia/métodos , Receptores Citoplasmáticos e Nucleares/fisiologia , Bioensaio/métodos , Genes Reporter/efeitos dos fármacos , Humanos , Programas de Rastreamento/métodos , Ligação Proteica , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo
2.
Cancer Res ; 82(3): 433-446, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34903600

RESUMO

Tumor-associated macrophages (TAM) are an important component of the tumor microenvironment (TME) that can promote tumor progression, metastasis, and resistance to therapies. Although TAMs represent a promising target for therapeutic intervention, the complexity of the TME has made the study of TAMs challenging. Here, we established a physiologically relevant in vitro TAM polarization system that recapitulates TAM protumoral activities. This system was used to characterize dynamic changes in gene expression and protein phosphorylation during TAM polarization and to screen phenotypic kinase inhibitors that impact TAM programming. BMS-794833, a multitargeted compound, was identified as a potent inhibitor of TAM polarization. BMS-794833 decreased protumoral properties of TAMs in vitro and suppressed tumor growth in mouse triple-negative breast cancer models. The effect of BMS-794833 was independent of its primary targets (MET and VEGFR2) but was dependent on its effect on multiple signaling pathways, including focal adhesion kinases, SRC family kinases, STAT3, and p38 MAPKs. Collectively, these findings underline the efficacy of polypharmacologic strategies in reprogramming complex signaling cascades activated during TAM polarization. SIGNIFICANCE: A physiologically relevant in vitro system of TAM polarization uncovers signaling pathways that regulate polarization and identifies strategies to target macrophage reprogramming to suppress cancer growth.


Assuntos
Macrófagos/metabolismo , Polifarmacologia/métodos , Macrófagos Associados a Tumor/efeitos dos fármacos , Animais , Feminino , Humanos , Camundongos , Microambiente Tumoral
3.
J Pharm Pharmacol ; 73(8): 1071-1079, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-33864464

RESUMO

OBJECTIVES: This study was designed to evaluate the pharmacological activity and therapeutic mechanism of Xiaojin Pills (XJW) on lung cancer. METHODS: Mice were orally administered with Xiaojin Pills for 21 days. Tumour samples were collected to evaluate the antilung cancer effect, and blood samples were collected to identify differential metabolites with metabolomics. Through the analysis of network pharmacology, the active ingredients and targets related to XJW therapy for lung cancer were filtered. KEY FINDINGS: Different expression of seven metabolites related to seven pathways, including Arachidonic acid metabolism, Citrate cycle, tryptophan metabolism, glyoxylate and dicarboxylate metabolism, arginine and proline metabolism, primary bile acid biosynthesis and nicotinate and nicotinamide metabolism, were demonstrated to explain the efficacy of XJW in the treatment of lung cancer. Furthermore, a total of 19 active ingredients (ursolic acid, α-thujone, pelargonidin, succinic acid, boswellic acid, muscone, daidzein, xanthorrhizol, isoeugenol, oleic acid, ß-caryophyllene, vanillin, ß-sitosterol, lupeol, palmitic acid, eugenol, methylbutenol, ß-elemene and quercetin) acted directly on 9 targets (CAT, PTGS2, PTGS1, CTH, ABTA, ALT1, ME2, AGXT and AGXT 2) and regulated 3 out of 7 metabolites (3-Hydroxyanthranilic acid, Pyruvate and Prostaglandin G2). CONCLUSIONS: Through metabolomics and network pharmacology analyses, this study demonstrated that the major metabolites of XJW in treating lung cancer were regulated by multitarget and multicomponent interaction network.


Assuntos
Produtos Biológicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Pulmonares , Metabolômica/métodos , Farmacologia em Rede/métodos , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/análise , Modelos Animais de Doenças , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Polifarmacologia/métodos , Transdução de Sinais/efeitos dos fármacos
4.
Semin Cancer Biol ; 68: 84-91, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-31698087

RESUMO

A pre-eminent subtype of lung carcinoma, Non-small cell lung cancer accounts for paramount causes of cancer-associated mortality worldwide. Undeterred by the endeavour in the treatment strategies, the overall cure and survival rates for NSCLC remain substandard, particularly in metastatic diseases. Moreover, the emergence of resistance to classic anticancer drugs further deteriorates the situation. These demanding circumstances culminate the need of extended and revamped research for the establishment of upcoming generation cancer therapeutics. Drug repositioning introduces an affordable and efficient strategy to discover novel drug action, especially when integrated with recent systems biology driven stratagem. This review illustrates the trendsetting approaches in repurposing along with their numerous success stories with an emphasize on the NSCLC therapeutics. Indeed, these novel hits, in combination with conventional anticancer agents, will ideally make their way the clinics and strengthen the therapeutic arsenal to combat drug resistance in the near future.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Neoplasias Pulmonares/tratamento farmacológico , Polifarmacologia/métodos , Animais , Humanos
5.
Semin Cancer Biol ; 68: 209-229, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32044472

RESUMO

Targeted drugs and precision medicine have transformed the landscape of cancer therapy and significantly improved patient outcomes in many cases. However, as therapies are becoming more and more tailored to smaller patient populations and acquired resistance is limiting the duration of clinical responses, there is an ever increasing demand for new drugs, which is not easily met considering steadily rising drug attrition rates and development costs. Considering these challenges drug repurposing is an attractive complementary approach to traditional drug discovery that can satisfy some of these needs. This is facilitated by the fact that most targeted drugs, despite their implicit connotation, are not singularly specific, but rather display a wide spectrum of target selectivity. Importantly, some of the unintended drug "off-targets" are known anticancer targets in their own right. Others are becoming recognized as such in the process of elucidating off-target mechanisms that in fact are responsible for a drug's anticancer activity, thereby revealing potentially new cancer vulnerabilities. Harnessing such beneficial off-target effects can therefore lead to novel and promising precision medicine approaches. Here, we will discuss experimental and computational methods that are employed to specifically develop single target and network-based off-target repurposing strategies, for instance with drug combinations or polypharmacology drugs. By illustrating concrete examples that have led to clinical translation we will furthermore examine the various scientific and non-scientific factors that cumulatively determine the success of these efforts and thus can inform the future development of new and potentially lifesaving off-target based drug repurposing strategies for cancers that constitute important unmet medical needs.


Assuntos
Antineoplásicos/uso terapêutico , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Polifarmacologia/métodos , Animais , Humanos
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