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1.
Proc Natl Acad Sci U S A ; 119(29): e2202015119, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858326

RESUMO

Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations; however, the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here, we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). Using our autochthonous mouse models, we found that Sox9 suppresses HGG growth and expands associated H3K27ac states, while promoting ZFTA-RELA (ZRFUS) EPN growth and diminishing H3K27ac states. These contrasting roles for Sox9 correspond with protein interactions with histone deacetylating complexes in HGG and an association with the ZRFUS oncofusion in EPN. Mechanistic studies revealed extensive Sox9 and ZRFUS promoter co-occupancy, indicating functional synergy in promoting EPN tumorigenesis. Together, our studies demonstrate how epigenomic states are differentially regulated in distinct subtypes of brain tumors, while revealing divergent roles for Sox9 in HGG and EPN tumorigenesis.


Assuntos
Neoplasias Encefálicas , Ependimoma , Epigênese Genética , Fatores de Transcrição SOX9 , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Ependimoma/genética , Ependimoma/patologia , Camundongos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/fisiologia
2.
J Enzyme Inhib Med Chem ; 37(1): 728-742, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35176963

RESUMO

The linking of ethacrynic acid with ethylenediamine and 1,4-butanediamine gave EDEA and BDEA, respectively, as membrane-permeable divalent pro-inhibitors of glutathione S-transferase (GST). Their divalent glutathione conjugates showed subnanomolar inhibition and divalence-binding to GSTmu (GSTM) (PDB: 5HWL) at ∼0.35 min-1. In cisplatin-resistant SK-OV-3, COC1, SGC7901 and A549 cells, GSTM activities probed by 15 nM BDEA or EDEA revealed 5-fold and 1.0-fold increases in cisplatin-resistant SK-OV-3 and COC1 cells, respectively, in comparison with the susceptible parental cells. Being tolerable by HEK293 and LO2 cells, BDEA at 0.2 µM sensitised resistant SK-OV-3 and COC1 cells by ∼3- and ∼5-folds, respectively, released cytochrome c and increased apoptosis; EDEA at 1.0 µM sensitised resistant SK-OV-3 and A549 cells by ∼5- and ∼7-fold, respectively. EDEA at 1.7 µg/g sensitised resistant SK-OV-3 cells to cisplatin at 3.3 µg/g in nude mouse xenograft model. BDEA and EDEA are promising leads for probing cellular GSTM and sensitising cisplatin-resistant ovarian cancers.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Ácido Etacrínico/farmacologia , Etilenodiaminas/farmacologia , Glutationa Transferase/antagonistas & inibidores , Neoplasias Ovarianas/tratamento farmacológico , Putrescina/farmacologia , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Etacrínico/química , Etilenodiaminas/química , Feminino , Glutationa Transferase/metabolismo , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Putrescina/química , Relação Estrutura-Atividade
3.
J Enzyme Inhib Med Chem ; 37(1): 652-665, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35109719

RESUMO

The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC50=25.6 µM, anti-angiogenesis in Zebrafish: IC50=38.4 µM, anti-proliferation against K562 and Jurkat: IC50=6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC50=4.8 µM and anti-angiogenesis in Zebrafish: IC50=3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC50= 0.09-1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Colchicina/antagonistas & inibidores , Indóis/farmacologia , Neovascularização Patológica/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Peixe-Zebra
4.
Dalton Trans ; 51(11): 4423-4428, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35195131

RESUMO

Metal phosphides have been proved to be potential theranostic agents of tumors. However, the limitations of single-modal imaging or the treatment effect of such materials need to be further improved. Here, we successfully prepared polyvinylpyrrolidone-modified bimetallic nickel cobalt phosphide (NiCoP/PVP) nanoparticles as a theranostic agent of tumors. Owing to the different types of magnetic properties of Ni and Co components, T1- and T2-weighted magnetic resonance imaging (MRI) could be simultaneously achieved to compensate the low accuracy brought about by single-modal MRI. In addition, NiCoP/PVP possesses excellent photothermal properties owing to its obvious absorption in the near-infrared (NIR) region, which endows NiCoP/PVP with high photothermal conversion efficiency (PCE) to serve as a photothermal agent for tumor ablation. Therefore, NiCoP/PVP is a promising theranostic agent for accurate diagnosis and effective treatment of tumors.


Assuntos
Antineoplásicos/farmacologia , Imageamento por Ressonância Magnética , Compostos Organometálicos/farmacologia , Fototerapia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Cobre/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Raios Infravermelhos , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Níquel/química , Níquel/farmacologia , Imagem Óptica , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Tamanho da Partícula , Fosfinas/química , Fosfinas/farmacologia , Povidona/química , Povidona/farmacologia , Nanomedicina Teranóstica
5.
Carbohydr Polym ; 278: 118941, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34973759

RESUMO

Self-assembled microparticles from chitosan (SAMC) was prepared by depolymerization induced by potassium persulfate. Particle size distribution data showed averaged around 5 µm size and SEM indicated the sequential formation of "RBC" shaped particles. Soluble SAMC consists of 'deacetylated' residues as revealed by 13C NMR. SAMC showed antitumor efficacy in human breast cancer cell lines through mitigation in cell proliferation, colony formation and cell migration. Anti-tumor and anti-angiogenic properties of SAMC was found in vivo Ehrlich ascites tumor (EAT) bearing mice model resulting in tumor growth inhibition (EAT control, 17.4 ml; SAMC treated, 6.8 ml) and improved survival potency (15 days). Moreover, the decrease in ascites VEGF secretion (EAT control, 1354 ng; SAMC treated, 351 ng) accompanied with reduction in neovessel formation. Apoptosis induction by SAMC was confirmed by DNA fragmentation, caspase activities and fluorescence staining methods respectively. SAMC may be a safe candidate for anti-tumor dietary supplement production in food industry.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma de Ehrlich/tratamento farmacológico , Quitosana/farmacologia , Neovascularização Patológica/tratamento farmacológico , Animais , Configuração de Carboidratos , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quitosana/síntese química , Quitosana/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/patologia
6.
Bioorg Med Chem Lett ; 61: 128552, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35051574

RESUMO

The transforming growth factor type ß receptor I (TGF-ß R1, also known as activin-like kinase 5 or ALK5) plays a significant role in the pathogenesis of multiple diseases such as malignant tumors and tissue fibrosis. Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. Herein, a novel series of 4-(pyridine-4-oxy)-3-(tetrahydro-2H-pyran-4-yl)-pyrazole derivatives was synthesized and identified as ALK5 inhibitors. Among them, compound 8h inhibited ALK5 autophosphorylation and NIH3T3 cell activity with IC50 values of 25 nM and 74.6 nM, respectively. Compound 8h also showed favorable pharmacokinetic profile and ameliorated hERG inhibition. More importantly, 30 mg/kg oral administration of 8h could significantly induce tumour growth inhibition in CT26 xenograft model without obvious toxicity.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Células NIH 3T3 , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Relação Estrutura-Atividade
7.
ACS Appl Mater Interfaces ; 14(4): 4914-4920, 2022 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-35050579

RESUMO

Electrodynamic therapy (EDT) and chemodynamic therapy (CDT) have the potential for future tumor treatment; however, their underlying applications are greatly hindered owing to their inherent drawbacks. The combination of EDT and CDT has been considered to be an effective way to maximize the superiorities of these two ROS-based methodologies. However, the development of novel nanomaterials with "one-for-all" functions still remains a big challenge. In this work, the polyoxometalate nanoparticles (NPs) were decorated using the zeolite imidazole framework (POM@ZIF-8) in order to integrate the EDT with CDT. The resulting POM@ZIF-8 NPs can effectively induce the generation of reactive oxygen species (ROS) via a catalytic reaction on the surface of POM NPs induced by an electric field (E). At the same time, POM@ZIF-8 NPs can catalyze the intracellular H2O2 into ROS via a Fenton-like reaction, thereby achieving the combination of EDT and CDT. Besides, since ZIF-8 is acid-responsive, it can protect normal tissues and avoid side effects. Of great note is that the cytotoxicity and the apoptosis rate of the POM@ZIF-8+E group (80%) were found to be significantly higher than that of the E group (55%). As a result, a high tumor inhibition phenomenon can be observed both in vitro and in vivo. The present study thus provides an alternative concept for combinational therapeutic modality with exceptional efficacy.


Assuntos
Ânions/farmacologia , Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Imidazóis/farmacologia , Polieletrólitos/farmacologia , Zeolitas/farmacologia , Animais , Ânions/química , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Imidazóis/química , Teste de Materiais , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Tamanho da Partícula , Polieletrólitos/química , Espécies Reativas de Oxigênio/metabolismo , Propriedades de Superfície , Microambiente Tumoral/efeitos dos fármacos , Zeolitas/química
8.
J Mater Sci Mater Med ; 33(1): 10, 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35022850

RESUMO

Herein we report synthesis of hematite (α-Fe2O3) nanorods by calcinating hydrothermally synthesized goethite nanorods at 5000C. The structural, optical and MRI imaging guided cancer therapeutic properties of fabricated nanorods have been discussed in this manscript. FESEM and TEM imaging techniques were used to confirm the nanorod like morphology of as prepared materials. As we know that Fe2O3 nanorods with size in the range of 25-30 nm exhibit super magnetism. After coating with the PEG, the as prepared nanorods can be used as T2 MR imaging contrast agents. An excellent T2 MRI contrast of 38.763 mM-1s-1 achieved which is highest reported so far for α-Fe2O3. Besides the as prepared nanorods display an excellent photothermal conversion efficiency of 39.5% thus acts as an excellent photothermal therapeutic agent. Thus, we envision the idea of testing our nanorods for photothermal therapy and MR imaging application both in vitro and in vivo, achieving an excellent T2 MRI contrast and photothermal therapy effect with as prepared PEGylated nanorods.


Assuntos
Compostos Férricos/química , Nanotubos/química , Animais , Materiais Biocompatíveis/química , Linhagem Celular , Sobrevivência Celular , Feminino , Compostos Férricos/toxicidade , Células HeLa , Humanos , Técnicas In Vitro , Imageamento por Ressonância Magnética , Teste de Materiais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Microscopia Eletrônica de Varredura , Nanotubos/toxicidade , Nanotubos/ultraestrutura , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Fototerapia/métodos , Polietilenoglicóis/química , Análise Espectral Raman , Difração de Raios X
9.
J Enzyme Inhib Med Chem ; 37(1): 379-385, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35012394

RESUMO

Elemene is a second-line broad-spectrum anti-tumour drug that has been used in China for more than two decades. However, its main anti-tumour ingredient, ß-elemene, has disadvantages, including excessive lipophilicity and relatively weak anti-tumour efficacy. To improve the anti-tumour activity of ß-elemene, based on its minor molecular weight character, we introduced furoxan nitric oxide (NO) donors into the ß-elemene structure and designed six series of new generation ß-elemene NO donor hybrids. The synthesised compounds could effectively release NO in vitro, displayed significant anti-proliferative effects on U87MG, NCI-H520, and SW620 cell lines. In the orthotopic glioma model, compound Id significantly and continuously suppressed the growth of gliomas in nude mice, and the brain glioma of the treatment group was markedly inhibited (>90%). In short, the structural fusion design of NO donor and ß-elemene is a feasible strategy to improve the in vivo anti-tumour activity of ß-elemene.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Óxido Nítrico/farmacologia , Oxidiazóis/farmacologia , Sesquiterpenos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glioma/patologia , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Óxido Nítrico/síntese química , Óxido Nítrico/química , Oxidiazóis/síntese química , Oxidiazóis/química , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-Atividade
10.
ACS Appl Mater Interfaces ; 14(2): 2650-2662, 2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-34995459

RESUMO

Smart nanotheranostic systems (SNSs) have attracted extensive attention in antitumor therapy. Nevertheless, constructing SNSs with disease diagnosis ability, improved drug delivery efficiency, inherent imaging performance, and high treatment efficiency remains a scientific challenge. Herein, ultrasmall tin dioxide (SnO2) was assembled with upconversion nanoparticles (UCNPs) to form mesoporous nanocapsules by an in situ hydrothermal deposition method, followed by loading with doxorubicin (DOX) and modification with bovine serum albumin (BSA). pH/near-infrared dual-responsive nanotheranostics was constructed for computed tomography (CT) and magnetic resonance (MR) imaging-induced collaborative cancer treatment. The mesoporous channel of SnO2 was utilized as a reservoir to encapsulate DOX, an antineoplastic drug, for chemotherapy and as a semiconductor photosensitizer for photodynamic therapy (PDT). Furthermore, the DOX-loaded UCNPs@SnO2-BSA nanocapsules combined PDT, Nd3+-doped UCNP-triggered hyperthermia effect, and DOX-triggered chemotherapy simultaneously and demonstrated prominently enhanced treatment efficiency compared to the monotherapy model. Moreover, tin, as one of the trace elements in the human body, has a similar X-ray attenuation coefficient to iodine and therefore can act as a contrast agent for CT imaging to monitor the treatment process. Such an orchestrated synergistic anticancer treatment exhibited apparent inhibition of tumor growth in tumor-bearing mice with negligible side effects. Our study demonstrates nanocapsules with excellent biocompatibility and great potential for cancer treatment.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Doxorrubicina/farmacologia , Nanocápsulas/química , Fármacos Fotossensibilizantes/farmacologia , Nanomedicina Teranóstica , Compostos de Estanho/farmacologia , Animais , Antibióticos Antineoplásicos/química , Materiais Biocompatíveis/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Teste de Materiais , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Porosidade , Soroalbumina Bovina/química , Propriedades de Superfície , Compostos de Estanho/química
11.
ACS Appl Mater Interfaces ; 14(3): 3809-3824, 2022 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-35015499

RESUMO

The local hyperthermia (>41 °C) effect of photothermal therapy (PTT) is significantly limited by the efficiency of PTT agents to convert laser energy to heat, and such oncotherapy, similar to conventional chemotherapy, invariably encounters the challenge of nonspecific application. Undue reliance on oxygen sources still poses particular difficulties in photodynamic therapy (PDT) for deep-level clinical applications. Considering these therapeutic issues, in this study, we constructed a versatile but unique nanosystem by encapsulating Au nanosheets in codoped gadolinium oxyfluoride (GdOF):Yb,Er spheres, followed by decoration of a chemotherapeutic drug (doxorubicin), photosensitizer (rose Bengal, RB), and targeted agent (folic acid). This allowed the incorporation of cancer treatment and real-time curative efficacy monitoring into one single theranostic nanoplatform. Benefiting from the dual contribution of the strong absorptions in the NIR-I and NIR-II regions, relevant photothermal-conversion efficiency (η) values pertaining to that final product were 39.2% at 1064 nm irradiation and 35.7% at 980 nm illumination. The fluorescence resonance energy transfer that occurred in the up-converted GdOF:Yb,Er to RB contributed to the high PDT efficacy. Combined with a micromeric acid-responsive drug release in a targeted tumor microenvironment, high-performance synergistic therapy was realized. In addition, up-conversion fluorescence imaging and computed tomography imaging accompanied by multimodal magnetic resonance imaging were simultaneously achieved owing to the doped lanthanide ions and the encapsulated Au nanosheets. Our designed oncotherapy nanosystem provides an alternative strategy to acquire ideal theranostic effects.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Doxorrubicina/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Fármacos Fotossensibilizantes/farmacologia , Nanomedicina Teranóstica , Animais , Antibióticos Antineoplásicos/química , Materiais Biocompatíveis/química , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Érbio/química , Érbio/farmacologia , Feminino , Flúor/química , Flúor/farmacologia , Gadolínio/química , Gadolínio/farmacologia , Células HeLa , Humanos , Raios Infravermelhos , Teste de Materiais , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Imagem Óptica , Óxidos/química , Óxidos/farmacologia , Fármacos Fotossensibilizantes/química , Microambiente Tumoral/efeitos dos fármacos , Itérbio/química , Itérbio/farmacologia
12.
Anticancer Agents Med Chem ; 22(3): 418-432, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33622230

RESUMO

The overwhelming global burden of cancer has posed numerous challenges and opportunities for developing anti-cancer therapies. Phytochemicals have emerged as promising synergistic compounds with potential anti-cancer effects to supplement chemo- and immune-therapeutic regimens. Anti cancer synergistic effects have been investigated in the interaction between phytocompounds derived from flavonoids such as quercetin, apigenin, kaempferol, hesperidin, emodin, etc., and conventional drugs. Xanthohumol is one of the prenylated phytoflavonoid that has demonstrated key anti-cancer activities in in vitro (anti proliferation of cancer cell lines) and in vivo (animal models of xenograft tumours) studies, and has been explored from different dimensions for targeting cancer subtypes. In the last decade, xanthohumol has been investigated how it induces the anti- cancer effects at cellular and molecular levels. The different signalling cascades and targets of xanthohumol are summarized in this review. Overall, this review summarizes the current advances made in the field of natural compounds with special reference to xanthohumol and its promising anti-cancer effects to inhibit tumour progression. The present review has also discussedthe potential of xanthohumol transitioning into a leadingcandidate from nano-therapy viewpoint along with the challenges which need to be addressed for extensive preclinical and clinical anti-cancer studies.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Flavonoides/farmacologia , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Propiofenonas/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Flavonoides/química , Humanos , Neoplasias/patologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Compostos Fitoquímicos/química , Propiofenonas/química
13.
Anticancer Agents Med Chem ; 22(1): 152-159, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34225636

RESUMO

BACKGROUND: MIR155HG is a long non-coding RNA (lncRNA) that has been shown to be dysregulated in a range of tumor types, but the functions of this lncRNA in melanoma remain to be explored. OBJECTIVES: We explored the functions of lncRNA MIR155HG in melanoma progression. METHODS: The expression of miR155HG was analyzed in clinical melanoma. Bioinformatics analysis was performed to assess the potential tumor-related functions of miR155HG. The interaction of miR155HG and SP1 and the inhibition of PSIP1 by miR-485-3p were analyzed by ChIP, luciferase reporter experiments, and the biological effects in melanoma were explored by colony formation assays, EdU cell proliferation assays, Transwell analysis, and intracranial melanoma mouse model. RESULTS: Herein, we found that MIR155HG was markedly upregulated in melanoma cell lines and tissues. We further determined that the SP1 transcription factor was responsible for driving MIR155HG upregulation in melanoma. Elevated MIR155HG levels were linked to decreased overall survival (OS) in melanoma patients, and we further determined that MIR155HG expression was an independent predictor of melanoma patient prognosis. When MIR155HG was knocked down in melanoma cells, this impaired their proliferative, migratory, and invasive activity. By using predictive bioinformatics analyses, we identified miR-485-3p as a microRNA (miRNA) capable of binding to both MIR155HG and the 3' UTR of PSIP1. CONCLUSION: Together, these results suggest that MIR155HG is capable of promoting melanoma cell proliferation via the miR-485-3p/PSIP1 axis. These novel findings provide new insights into the development of melanoma, potentially highlighting future avenues for therapeutic intervention.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Melanoma/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Fator de Transcrição Sp1/metabolismo , Fatores de Transcrição/metabolismo , Regulação para Cima , Animais , Movimento Celular , Proliferação de Células , Feminino , Humanos , Melanoma/patologia , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , RNA Longo não Codificante/genética , Software , Células Tumorais Cultivadas
14.
Acta Pharmacol Sin ; 43(1): 209-219, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33782541

RESUMO

PI3Kδ is expressed predominately in leukocytes and overexpressed in B-cell-related malignances. PI3Kδ has been validated as a promising target for cancer therapy, and specific PI3Kδ inhibitors were approved for clinical practice. However, the substantial toxicity and relatively low efficacy as a monotherapy in diffuse large B-cell lymphoma (DLBCL) limit their clinical use. In this study, we described a novel PI3Kδ inhibitor SAF-248, which exhibited high selectivity for PI3Kδ (IC50 = 30.6 nM) over other PI3K isoforms at both molecular and cellular levels, while sparing most of the other human protein kinases in the kinome profiling. SAF-248 exhibited superior antiproliferative activity against 27 human lymphoma and leukemia cell lines compared with the approved PI3Kδ inhibitor idelalisib. In particular, SAF-248 potently inhibited the proliferation of a panel of seven DLBCL cell lines (with GI50 values < 1 µM in 5 DLBCL cell lines). We demonstrated that SAF-248 concentration-dependently blocked PI3K signaling followed by inducing G1 phase arrest and apoptosis in DLBCL KARPAS-422, Pfeiffer and TMD8 cells. Its activity against the DLBCL cells was negatively correlated to the protein level of PI3Kα. Oral administration of SAF-248 dose-dependently inhibited the growth of xenografts derived from Pfeiffer and TMD8 cells. Activation of mTORC1, MYC and JAK/STAT signaling was observed upon prolonged treatment and co-targeting these pathways would potentiate the activity of SAF-248. Taken together, SAF-248 is a promising selective PI3Kδ inhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy.


Assuntos
Antineoplásicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Fosfoinositídeo-3 Quinase/química , Relação Estrutura-Atividade
15.
Acta Pharmacol Sin ; 43(1): 220-228, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33782542

RESUMO

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.


Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Regulação para Baixo/efeitos dos fármacos , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/deficiência , Quinase 1 do Ponto de Checagem/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
16.
Eur J Med Chem ; 227: 113916, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34678573

RESUMO

Based on previous reports on the significance of halogen moieties and the indenopyridin-5-one skeleton, we designed and synthesized a novel series of halogen (F-, Cl-, Br-, CF3- and OCF3-)-containing 2,4-diphenyl indenopyridin-5-ones and their corresponding -5-ols. Unlike indenopyridin-5-ols, most of the prepared indenopyridin-5-ones with Cl-, Br-, and CF3- groups at the 2-phenyl ring conferred a strong dual topoisomerase I/IIα inhibitory effect. Among the series, para-bromophenyl substituted compound 9 exhibited the most potent topoisomerase inhibition and antiproliferative effects, which showed dependency upon the topoisomerase gene expression level of diverse cancer cells. In particular, as a DNA minor groove-binding non-intercalative topoisomerase I/IIα catalytic inhibitor, compound 9 synergistically promoted the anticancer efficacy of clinically applied topoisomerase I/IIα poisons both in vitro and in vivo, having the great advantage of alleviating poison-related toxicities.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Halogênios/farmacologia , Indenos/farmacologia , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Piridonas/farmacologia , Inibidores da Topoisomerase/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Halogênios/química , Humanos , Indenos/síntese química , Indenos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piridonas/síntese química , Piridonas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química , Células Tumorais Cultivadas
17.
Eur J Med Chem ; 227: 113891, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34656042

RESUMO

TumorSelect® is an anticancer technology that combines cytotoxics, nanotechnology, and knowledge of human physiology to develop innovative therapeutic interventions with minimal undesirable side effects commonly observed in conventional chemotherapy. Tumors have a voracious appetite for cholesterol which facilitates tumor growth and fuels their proliferation. We have transformed this need into a stealth delivery system to disguise and deliver anticancer drugs with the assistance of both the human body and the tumor cell. Several designer prodrugs are incorporated within pseudo-LDL nanoparticles, which carry them to tumor tissues, are taken up, internalized, transformed into active drugs, and inhibit cancer cell proliferation. Highly lipophilic prodrug conjugates of paclitaxel suitable for incorporation into the pseudo-LDL nanoparticles of the TumorSelect® delivery vehicle formulation were designed, synthesized, and evaluated in the panel of 24-h NCI-60 human tumor cell line screening to demonstrate the power of such an innovative approach. Taxane prodrugs, viz., ART-207 was synthesized by tethering paclitaxel to lipid moiety with the aid of a racemic solketal as a linker in cost-effective, simple, and straightforward synthetic transformations. In addition to the typical 24-h NCI screening protocol, these compounds were assessed for growth inhibition or killing of ovarian cell lines for 48 and 72h-time intervals and identified the long-lasting effectiveness of these lipophilic prodrugs. All possible, enantiomerically pure isomers of ART-207 were also synthesized, and cytotoxicities were biosimilar to racemic ART-207, suggesting that enantiopurity of linker has a negligible effect on cell proliferation. To substantiate further, ART-207 was evaluated for its in vivo tumor reduction efficacy by studying the xenograft model of ovarian cancer grown in SCID mice. Reduced weight loss (a measure of toxicity) in the ART-207 group was observed, even though it was dosed at 2.5x the paclitaxel equivalent of Abraxane®. As a result, our delineated approach is anticipated to improve patient quality of life, patient retention in treatment regimes, post-treatment rapid recovery, and overall patient compliance without compromising the efficacy of the cytotoxic promiscuous natural products.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Paclitaxel/farmacologia , Pró-Fármacos/farmacologia , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos NOD , Camundongos SCID , Conformação Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Paclitaxel/síntese química , Paclitaxel/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Eur J Med Chem ; 227: 113893, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34656899

RESUMO

The equilibrium between histone acetylation and deacetylation plays an important role in cancer initiation and progression. The histone deacetylases (HDACs) are a class of key regulators of gene expression that enzymatically remove an acetyl moiety from acetylated lysine ε-amino groups on histone tails. Therefore, HDAC inhibitors have recently emerged as a promising strategy for cancer therapy and several pan-HDAC inhibitors have globally been approved for clinical use. In the present study, we designed and synthesized a series of substituted indole-based hydroxamic acid derivatives that exhibited potent anti-proliferative activities in various tumor cell lines. Among the compounds tested, compound 4o, was found to be among the most potent in the inhibition of HDAC1 (half maximal inhibitory concentration, IC50 = 1.16 nM) and HDAC6 (IC50 = 2.30 nM). It also exhibited excellent in vitro anti-tumor proliferation activity. Additionally, compound 4o effectively increased the acetylation of histone H3 in a dose-dependent manner and inhibited cell proliferation by inducing cell cycle arrest and apoptosis. Moreover, compound 4o remarkably blocked colony formation in HCT116 cancer cells. Based on its favorable in vitro profile, compound 4o was further evaluated in an HCT116 xenograft mouse model, in which it demonstrated better in vivo efficacy than the clinically used HDAC inhibitor, suberanilohydroxamic acid. Interestingly, compound 4k was found to have a preference for the inhibition of HDAC6, with IC50 values of 115.20 and 5.29 nM against HDAC1 and HDAC6, respectively.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Histona Desacetilase 1/antagonistas & inibidores , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 1/metabolismo , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Indóis/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
Eur J Med Chem ; 227: 113908, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34656900

RESUMO

Highly efficacious and tolerable agents for the treatment of glioblastoma (GBM), the most common and aggressive primary brain tumor, are urgently needed. Herein, we reveal the design, synthesis and biological evaluation of several piperazine based benzamide derivatives, which are based on the non-classical isostere principle and combination principle for GBM therapy. After structure-activity relationship (SAR) study, compound L19 was demonstrated as the most promising compound with IC50 values of 0.15 µM, 0.29 µM, 1.25 µM against GBM C6, U87-MG, U251 cells, respectively. Moreover, compound L19 could inhibit the proliferation, migration and invasion, as well as induce apoptosis and cell cycle arrest of GBM cell lines in vitro. From mechanism perspective, compound L19 could regulate the cell cycle-related proteins and influence the p16INK4a-CDK4/6-pRb pathway by western blotting experiment. What is worth mentioning is that compound L19 could penetrate the blood-brain barrier (BBB) with an exceptional brain-to-plasma ratio of 1.07 in vivo. Besides, the superior anti-glioblastoma potency in vivo of compound L19 was identified on U87-MG-xenograft model without any apparent host toxicity. Overall, the potential of compound L19 warrants further pre-clinical investigation for GBM therapy.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Glioblastoma/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Piperazinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piperazinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Células Tumorais Cultivadas
20.
Genes Genomics ; 44(1): 123-131, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34697761

RESUMO

BACKGROUND: Previously, we published that 4'-azid-2'-deoxy-2'-fluorarabinoside (FNC), a novel cytosine nucleoside analog, has good anti-viral and anti-tumor activity. OBJECTIVE: This study aimed to further explore the role and molecular mechanism of FNC in non-small cell lung cancer (NSCLC). METHODS: FNC was tested in the NSCLC H460 cell line, the Lewis mouse model, and the H460 cell xenograft model. The effects of FNC were assessed by cell viability, transwell migration, and wound scratch analyses of cell migration and invasion. Apoptosis was assessed by flow cytometry. Proteins expression was assessed by western blot and immunohistochemistry staining (IHC). RESULTS: FNC inhibits the proliferation and metastasis of H460 cells in a time- and dose-dependent manner. FNC treatment showed efficacy and low toxicity in the Lewis mouse lung cancer model as well as in the H460 cell xenograft model. Further, FNC induced H460 cell apoptosis through the activation of the mitochondrial pathway. Notably, FNC inhibited invasion by increasing E-cadherin protein and reducing the protein expression of VEGF, MMP-2, MMP-9, and CD31. CONCLUSION: FNC inhibits NSCLC by activating the mitochondrial apoptosis pathway and regulating the expressions of multiple proteins related to cell adhesion and invasion, highlighting its potential as an NSCLC therapeutic.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Nucleotídeos de Citosina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Experimentais/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Caderinas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Nucleotídeos de Citosina/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Transdução de Sinais/efeitos dos fármacos
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