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1.
Nat Commun ; 10(1): 4349, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554791

RESUMO

Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFß receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFß signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFß receptor stabilisation. This upregulation of the TGFß pathway by HGF leads to TGFß-mediated EMT and invasion. In vivo we show that TGFß receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFß and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-met/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Neoplasias da Bexiga Urinária/genética , Animais , Benzamidas/farmacologia , Linhagem Celular Tumoral , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
2.
Nat Commun ; 10(1): 4363, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554794

RESUMO

The LKB1/AMPK pathway plays a major role in cellular homeostasis and tumor suppression. Down-regulation of LKB1/AMPK occurs in several human cancers and has been implicated in metabolic diseases. However, the precise upstream regulation of LKB1-AMPK pathway is largely unknown. Here, we report that AMPK activation by LKB1 is regulated by tankyrases. Tankyrases interact with and ribosylate LKB1, promoting its K63-linked ubiquitination by an E3 ligase RNF146, which blocks LKB1/STRAD/MO25 complex formation and LKB1 activation. LKB1 activation by tankyrase inhibitors induces AMPK activation and suppresses tumorigenesis. Similarly, the tankyrase inhibitor G007-LK effectively regulates liver metabolism and glycemic control in diabetic mice in a LKB1-dependent manner. In patients with lung cancer, tankyrase levels negatively correlate with p-AMPK levels and poor survival. Taken together, these findings suggest that tankyrase and RNF146 are major up-stream regulators of LKB1-AMPK pathway and provide another focus for cancer and metabolic disease therapies.


Assuntos
Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tanquirases/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Células HeLa , Homeostase/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sulfonas/farmacologia , Tanquirases/metabolismo , Triazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , para-Aminobenzoatos/farmacologia
3.
Nat Commun ; 10(1): 4355, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554797

RESUMO

Genetically engineered T cells expressing a chimeric antigen receptor (CAR) are rapidly emerging a promising new treatment for haematological and non-haematological malignancies. CAR-T therapy can induce rapid and durable clinical responses but is associated with unique acute toxicities. Moreover, CAR-T cells are vulnerable to immunosuppressive mechanisms. Here, we report that CAR-T cells release extracellular vesicles, mostly in the form of exosomes that carry CAR on their surface. The CAR-containing exosomes express a high level of cytotoxic molecules and inhibit tumour growth. Compared with CAR-T cells, CAR exosomes do not express Programmed cell Death protein 1 (PD1), and their antitumour effect cannot be weakened by recombinant PD-L1 treatment. In a preclinical in vivo model of cytokine release syndrome, the administration of CAR exosomes is relatively safe compared with CAR-T therapy. This study supports the use of exosomes as biomimetic nanovesicles that may be useful in future therapeutic approaches against tumours.


Assuntos
Exossomos/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Exossomos/metabolismo , Humanos , Ativação Linfocitária/imunologia , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Neoplasias/genética , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo
4.
Nat Commun ; 10(1): 4397, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562301

RESUMO

Strand-selection is the final step of microRNA biogenesis in which functional mature miRNAs are generated from one or both arms of precursor. The preference of strand-selection is diverse during development and tissue formation, however, its pathological effect is still unknown. Here we find that two miRNA arms from the same precursor, miR-574-5p and miR-574-3p, are inversely expressed and play exactly opposite roles in gastric cancer progression. Higher-5p with lower-3p expression pattern is significantly correlated with higher TNM stages and poor prognosis of gastric cancer patients. The increase of miR-574-5p/-3p ratio, named miR-574 arm-imbalance is partially due to the dynamic expression of their highly complementary targets in gastric carcinogenesis, moreover, the arm-imbalance of miR-574 is in turn involved and further promotes gastric cancer progression. Our results indicate that miR-574 arm-imbalance contribute to gastric cancer progression and re-modification of the miR-574-targets homeostasis may represent a promising strategy for gastric cancer therapy.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Gástricas/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Interferência de RNA , Terapêutica com RNAi/métodos , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
5.
Nat Commun ; 10(1): 4418, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562357

RESUMO

Smart drug delivery systems (SDDSs) for cancer treatment are of considerable interest in the field of theranostics. However, developing SDDSs with early diagnostic capability, enhanced drug delivery and efficient biodegradability still remains a scientific challenge. Herein, we report near-infrared light and tumor microenvironment (TME), dual responsive as well as size-switchable nanocapsules. These nanocapsules are made of a PLGA-polymer matrix coated with Fe/FeO core-shell nanocrystals and co-loaded with chemotherapy drug and photothermal agent. Smartly engineered nanocapsules can not only shrink and decompose into small-sized nanodrugs upon drug release but also can regulate the TME to overproduce reactive oxygen species for enhanced synergistic therapy in tumors. In vivo experiments demonstrate that these nanocapsules can target to tumor sites through fluorescence/magnetic resonance imaging and offer remarkable therapeutic results. Our synthetic strategy provides a platform for next generation smart nanocapsules with enhanced permeability and retention effect, multimodal anticancer theranostics, and biodegradability.


Assuntos
Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Raios Infravermelhos/uso terapêutico , Nanocápsulas/química , Neoplasias/terapia , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Nanopartículas/química , Neoplasias/metabolismo , Neoplasias/patologia , Polímeros/química , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
6.
Drug Deliv ; 26(1): 886-897, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31524012

RESUMO

The aim of this study is to construct a SYL3C aptamer-anchored microemulsion based on ß-elemene and PTX (SYL3C/EP-MEs) for enhancement on colorectal cancer therapy. Such microemulsion is consist of encapsulated drugs (ß-elemene and PTX), tumor targeting ligand (3'-end thiolated SYL3C aptamer), thiol conjugated site (maleimide-modified PEGylated 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, mal-DOPE-PEG), pH-sensitive component (DOPE) and other necessary excipients. SYL3C/EP-MEs showed a spherical particle with an average particle size around 30 nm and a high encapsulation efficiency (>80%) for both drugs. ß-elemene and PTX could be released controllably from SYL3C/EP-MEs as pH values changed. SYL3C/EP-MEs displayed a selective affinity to HT-29 cells, leading to an obvious increase in cellular uptake, cell apoptosis and cytotoxicity. In the HT-29 tumor xenograft-bearing nude mice model studies, SYL3C/EP-MEs showed an overwhelming tumor growth inhibition, the longest survival time and the lowest systemic toxicity among all the treatments. The potential mechanism of enhanced anti-cancer ability was probably associated with the induction of M1 macrophage polarization, the downregulation of mutant p53 protein and the reduction of bcl-2 protein expression. Collectively, the microemulsion codelivery of ß-elemene and PTX using functionalization with SYL3C aptamer provides a novel approach for combinational colorectal cancer-targeted treatment.


Assuntos
Aptâmeros de Nucleotídeos/química , Neoplasias Colorretais/tratamento farmacológico , Emulsões/química , Emulsões/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
7.
Nat Commun ; 10(1): 3981, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484922

RESUMO

The diverse expression pattern of CD36 reflects its multiple cellular functions. However, the roles of CD36 in colorectal cancer (CRC) remain unknown. Here, we discover that CD36 expression is progressively decreased from adenomas to carcinomas. CD36 loss predicts poor survival of CRC patients. In CRC cells, CD36 acts as a tumor suppressor and inhibits aerobic glycolysis in vitro and in vivo. Mechanically, CD36-Glypcian 4 (GPC4) interaction could promote the proteasome-dependent ubiquitination of GPC4, followed by inhibition of ß-catenin/c-myc signaling and suppression of downstream glycolytic target genes GLUT1, HK2, PKM2 and LDHA. Moreover, disruption of CD36 in inflammation-induced CRC model as well as ApcMin/+ mice model significantly increased colorectal tumorigenesis. Our results reveal a CD36-GPC4-ß-catenin-c-myc signaling axis that regulates glycolysis in CRC development and may provide an intervention strategy for CRC prevention.


Assuntos
Antígenos CD36/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Glicólise/genética , Glipicanas/genética , Proteínas Proto-Oncogênicas c-myc/genética , beta Catenina/genética , Idoso , Animais , Antígenos CD36/metabolismo , Células CACO-2 , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Feminino , Perfilação da Expressão Gênica/métodos , Glipicanas/metabolismo , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-myc/metabolismo , Terapêutica com RNAi/métodos , Transdução de Sinais/genética , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , beta Catenina/metabolismo
8.
Nat Commun ; 10(1): 3979, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484926

RESUMO

One largely unknown question in cell biology is the discrimination between inconsequential and functional transcriptional events with relevant regulatory functions. Here, we find that the oncofetal HMGA2 gene is aberrantly reexpressed in many tumor types together with its antisense transcribed pseudogene RPSAP52. RPSAP52 is abundantly present in the cytoplasm, where it interacts with the RNA binding protein IGF2BP2/IMP2, facilitating its binding to mRNA targets, promoting their translation by mediating their recruitment on polysomes and enhancing proliferative and self-renewal pathways. Notably, downregulation of RPSAP52 impairs the balance between the oncogene LIN28B and the tumor suppressor let-7 family of miRNAs, inhibits cellular proliferation and migration in vitro and slows down tumor growth in vivo. In addition, high levels of RPSAP52 in patient samples associate with a worse prognosis in sarcomas. Overall, we reveal the roles of a transcribed pseudogene that may display properties of an oncofetal master regulator in human cancers.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Proteínas/genética , Pseudogenes/genética , Proteínas de Ligação a RNA/genética , Transdução de Sinais/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica/métodos , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Humanos , Estimativa de Kaplan-Meier , Células MCF-7 , Camundongos Nus , Proteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Terapêutica com RNAi/métodos , Transcrição Genética , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Proteínas ras/genética , Proteínas ras/metabolismo
9.
Respir Res ; 20(1): 164, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331328

RESUMO

BACKGROUND: Approximately 30% of patients with epidermal growth factor receptor (EGFR)-activating mutations have no response to EGFR-tyrosine kinase inhibitors (TKIs) (primary resistance). However, little is known about the molecular mechanism involved in primary resistance to EGFR-TKIs in EGFR-mutant non-small cell lung cancer (NSCLC). Programmed death ligand-1 (PD-L1) plays important regulatory roles in intracellular functions and leads to acquired resistance to EGFR-TKIs in NSCLC. Here, we investigated the mechanistic role of PD-L1 in primary resistance to EGFR-TKIs in EGFR-mutant NSCLC cells. METHODS: The expression levels of PD-L1 and the sensitivity to gefitinib in H1975, HCC827 and PC-9 cells were determined by quantitative real-time PCR analysis (qRT-PCR) and Cell Counting Kit-8 (CCK-8) assays, respectively. Molecular manipulations (silencing or overexpression) were performed to assess the effect of PD-L1 on sensitivity to gefitinib, and a mouse xenograft model was used for in vivo confirmation. Western blotting and qRT-PCR were used to analyse the expression of epithelial-mesenchymal transition (EMT) markers. The effect of PD-L1 on migratory and invasive abilities was evaluated using the Transwell assay and mice tail intravenous injection. RESULTS: Higher expression of PD-L1 was related to less sensitivity to gefitinib in EGFR-mutant NSCLC cell lines. The overexpression or knockdown of PD-L1 presented diametrical sensitivity to gefitinib in vitro and in vivo. Furthermore, the overexpression of PD-L1 led to primary resistance to gefitinib through the induction of EMT, which was dependent on the upregulation of Smad3 phosphorylation. Moreover, in the mouse model, the knockdown of PD-L1 inhibited transforming growth factor (TGF)-ß1-induced cell metastasis in vivo. CONCLUSION: PD-L1 contributes to primary resistance to EGFR-TKI in EGFR-mutant NSCLC cells, which may be mediated through the induction of EMT via the activation of the TGF-ß/Smad canonical signalling pathway.


Assuntos
Antígeno B7-H1/biossíntese , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptores ErbB/biossíntese , Neoplasias Pulmonares/metabolismo , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Células HEK293 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mutação/efeitos dos fármacos , Mutação/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteínas Smad/genética , Fator de Crescimento Transformador beta/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
10.
Carbohydr Polym ; 222: 114993, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31320068

RESUMO

ß-glucans trigger the proinflammatory responses of innate immune cells to enhance the host defense. A variety of ß-glucans were identified as strong immune stimulator and exerted antitumor activities. Our previous work indicates that a ß-1,3/1,6-glucan (BG136) derived from marina alga Durvillaea antarctica promotes the proinflammatory responses in macrophage cell line RAW264.7. In the present study, we further explored its antitumor effects in vivo as an immune stimulator. The data shows that BG136 alone decreases the tumor burdens in DLD1 xenograft and AOM-DSS induced tumor models. BG136 also augments the antitumor effects of PD-1 antibody in B16 syngeneic tumor model. BG136 increases macrophage phagocytosis, enhances cytokine/chemokine secretion and modulates the systemic and intratumoral immune cell composition. Collectively, these data suggest that BG136 might act as an immune stimulator to exert antitumor effects in vivo.


Assuntos
Adjuvantes Imunológicos/farmacologia , Glucanos/farmacologia , Neoplasias/imunologia , Animais , Linhagem Celular Tumoral , Citocinas/imunologia , Humanos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Feófitas/metabolismo , Fagocitose/efeitos dos fármacos , Receptor de Morte Celular Programada 1/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
Carbohydr Polym ; 219: 143-154, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151511

RESUMO

In recent years, the utilization of polysaccharides as targeted drug carriers has attracted considerable attention. Herein, Angelica sinensis polysaccharide (ASP), a plant polysaccharide with good biocompatibility, excellent aqueous solubility and intrinsic liver-targeted capability, was modified with hydrophobic group (deoxycholic acid) to fabricate amphiphilic conjugate (ASP-DOCA). Self-assembled nanoparticles were successfully developed for hepatoma-targeted delivery of therapeutic drug doxorubicin (DOX). The DOX loaded nanoparticles (DOX/ASP-DOCA NPs) were spherical in shape with a particle size of 228 nm and negatively charged around -17 mV. DOX was released from nanoparticles in a sustainable and pH-dependent manner. In vitro cellular uptake revealed that DOX/ASP-DOCA NPs were internalized into HepG2 cells through asialoglycoprotein receptor (ASGPR)-mediated endocytosis, resulting in a higher anti-proliferation effect than DOX-loaded dextran derivative DOX/DEX-DOCA NPs. Additionally, DOX/ASP-DOCA NPs showed higher inhibition on the growth of HepG2 multicellular spheroids (MCs) than DOX/DEX-DOCA NPs. In vivo imaging demonstrated that ASP-DOCA NPs specifically targeted HepG2 tumors via ASGPR, improving the accumulation of DOX/ASP-DOCA NPs in tumors and generating superior antitumor activity compared with free DOX and DOX/DEX-DOCA NPs. Taken together, ASP-DOCA NPs possess potential applications in drug delivery systems targeting liver cancer.


Assuntos
Angelica sinensis/metabolismo , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Nanoconjugados/uso terapêutico , Nanopartículas/uso terapêutico , Polissacarídeos/uso terapêutico , Animais , Receptor de Asialoglicoproteína/metabolismo , Ácido Desoxicólico/química , Células HeLa , Células Hep G2 , Humanos , Camundongos , Nanopartículas/ultraestrutura , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
12.
Biomed Pharmacother ; 117: 109093, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31200257

RESUMO

Liposarcoma (LS) is a chemotherapy-resistant disease. The aim of the present study was to find precise therapy for a recurrent dedifferentiated liposarcoma (DDLS) in a patient-derived orthotopic xenograft (PDOX) model. The DDLS PDOX models were established orthotopically in the right inguinal area of nude mice. The DDLS PDOX models were randomized into five groups: untreated; doxorubicin (DOX); gemcitabine (GEM) combined with docetaxel (DOC); pazopanib (PAZ); and yondelis (YON). On day 15, all mice were sacrificed. Measurement of tumor volume and body weight were done two times a week. The DDLS PDOX was resistant to DOX (P > 0.184). YON suppressed tumor growth significantly compared to control group (P < 0.027). However, only GEM combined with DOC arrested the tumor growth (P < 0.001). These findings suggest that GEM combined with DOC has clinical potential for this and possibly other DDLS patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/análogos & derivados , Docetaxel/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lipossarcoma/tratamento farmacológico , Animais , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Xenoenxertos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia/tratamento farmacológico , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
Biomed Pharmacother ; 117: 109091, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31228803

RESUMO

Diosmetin is a natural flavonoid obtained from citrus fruits and some medicinal herbs. Previous studies have reported the anti-cancer activity of diosmetin in some types of tumors. However, it is still unclear whether diosmetin exerts anti-cancer effects, particularly anti-angiogenic effects, in skin cancer. In this study, we used B16F10 melanoma cells and human umbilical vein endothelial cells to investigate the inhibitory effect of diosmetin on cell proliferation, migration and tube formation in vitro. Rat aorta ring assays were performed to determine the effect of diosmetin on ECs sprouting ex vivo. Furthermore, a B16F10 mouse melanoma model was used to observe the effect of diosmetin on tumor growth, angiogenesis, and metastasis in vivo. Our results showed that diosmetin not only suppressed tumor cell proliferation and migration but also induced cell apoptosis via the caspase pathway in B16F10 cells, and potently inhibited tube formation and cell migration in HUVECs. Rat aorta ring assays showed that diosmetin attenuated the ECs sprouting. Moreover, the mouse melanoma model showed that diosmetin significantly delayed tumor growth by inhibiting tumor vessels sprouting and expansion during tumor progression. Notably, diosmetin induced the normalization of tumor vasculature through the downregulation of angiopoietin-2 and the improvement of pericyte coverage, leading to suppression of metastasis formation in lungs and lymph nodes. In conclusion, our results demonstrate that diosmetin suppresses tumor progression and metastasis by inducing tumor cell death and inhibiting tumor angiogenesis as well as normalizing the defective tumor vasculature, suggesting that diosmetin is a potential adjuvant chemotherapy agent.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Flavonoides/farmacologia , Neovascularização Patológica/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Metástase Linfática/tratamento farmacológico , Metástase Linfática/patologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/patologia , Ratos , Ratos Sprague-Dawley , Neoplasias Cutâneas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
14.
Int J Cancer ; 145(9): 2535-2546, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241175

RESUMO

Despite its anticipated clinical potential, anti-PD-1 immunotherapy has only yielded poor outcomes in recent clinical trials for glioblastoma patients. Strategies combining anti-PD-1 antibody with other treatment modalities are being explored to alter the immunosuppressive microenvironment that appears to characterize these anti-PD-1-insensitive tumors. Here, we evaluated whether introducing wild-type p53 gene via a tumor-targeting nanomedicine (termed SGT-53) could provide immune stimulation and augment anti-PD-1 therapy in mouse syngeneic GL261 tumor models (either subcutaneous or intracranial). In both models, anti-PD-1 monotherapy had no demonstrable therapeutic effect. However, combining anti-PD-1 with our investigational nanomedicine SGT-53 was very effective in inhibiting tumor growth, inducing tumor cell apoptosis and increasing intratumoral T-cell infiltration. A significant survival benefit was observed in mice bearing intracranial glioblastoma receiving combination treatment. Importantly, SGT-53 upregulated PD-L1 expression both in vitro and in vivo. Transcriptome analysis revealed modulation of genes linked to either cancer progression or immune activation after combination treatment. Our data suggest that SGT-53 can boost antitumor immunity and sensitize glioblastoma to anti-PD-1 therapy by converting immunologically "cold" tumors into "hot" tumors. Combining SGT-53 with anti-PD-1 might benefit more patients from anti-PD-1 immunotherapy and our data support evaluation of this combination in patients with glioblastoma.


Assuntos
Barreira Hematoencefálica/metabolismo , Genes p53/genética , Glioblastoma/genética , Receptor de Morte Celular Programada 1/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Terapia Combinada/métodos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/imunologia , Glioblastoma/terapia , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BL , Nanomedicina/métodos , Células RAW 264.7 , Linfócitos T/patologia , Transcriptoma/genética , Microambiente Tumoral/genética , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
15.
Mar Drugs ; 17(6)2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31248066

RESUMO

Lectins display a variety of biological functions including insecticidal, antimicrobial, as well as antitumor activities. In this report, a gene encoding Aphrocallistes vastus lectin (AVL), a C-type lectin, was inserted into an oncolytic vaccinia virus vector (oncoVV) to form a recombinant virus oncoVV-AVL, which showed significant in vitro antiproliferative activity in a variety of cancer cell lines. Further investigations revealed that oncoVV-AVL replicated faster than oncoVV significantly in cancer cells. Intracellular signaling elements including NF-κB2, NIK, as well as ERK were determined to be altered by oncoVV-AVL. Virus replication upregulated by AVL was completely dependent on ERK activity. Furthermore, in vivo studies showed that oncoVV-AVL elicited significant antitumor effect in colorectal cancer and liver cancer mouse models. Our study might provide insights into a novel way of the utilization of marine lectin AVL in oncolytic viral therapies.


Assuntos
Antineoplásicos/farmacologia , Lectinas/genética , Lectinas/farmacologia , Vírus Oncolíticos/genética , Poríferos/genética , Vírus Vaccinia/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Feminino , Células HCT116 , Células HEK293 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia Viral Oncolítica/métodos , Transdução de Sinais/efeitos dos fármacos , Replicação Viral/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Cancer Sci ; 110(8): 2493-2506, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215139

RESUMO

Gallbladder cancer (GBC) is the most common malignancy of the bile duct and has a high mortality rate. Here, we demonstrated that BRD4 inhibitor JQ1 and histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) synergistically inhibited the GBC cells in vitro and in vivo. Our results showed that cotreatment with JQ1 and SAHA significantly inhibited proliferation, cell viability and metastasis, and induced apoptosis and G2/M arrest in GBC cells, with only minor effects in benign cells. In vivo, tumor volumes and weights of GBC xenograft models were significantly decreased after treatment with JQ1 or SAHA; meanwhile, the cotreatment showed the strongest effect. Further study indicated that the above anticancer effects was associated with the downregulation of BRD4 and suppression of PI3K/AKT and MAPK/ERK pathways. These findings highlight JQ1 and SAHA as potential therapeutic agents and their combination as a promising therapeutic strategy for GBC.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias da Vesícula Biliar/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Neoplasias da Vesícula Biliar/patologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Vorinostat/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
17.
BMC Cancer ; 19(1): 424, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064330

RESUMO

BACKGROUND: pressurized intraperitoneal aerosol chemotherapy (PIPAC), with or without electrostatic precipitation (ePIPAC), was recently introduced in the treatment of peritoneal metastases (PM) from ovarian cancer (OC). Preliminary clinical data are promising, but several methodological issues as well the anticancer efficacy of PIPAC remain unaddressed. Here, we propose a rat ePIPAC model that allows to study these issues in a clinically relevant, reproducible, and high throughput model. METHODS: laparoscopy and PIPAC were established in healthy Wistar rats. Aerosol properties were measured using laser diffraction spectrometry based granulometric analyses. Electrostatic precipitation was accomplished using a commercially available generator (Ultravision™). A xenograft model of ovarian PM was created in athymic rats using intraperitoneal (IP) injection of SKOV-3 luciferase positive cells. Tumor growth was monitored weekly by in vivo bioluminescence imaging. RESULTS: PIPAC and electrostatic precipitation were well tolerated using a capnoperitoneum of 8 mmHg. All rats survived the (e)PIPAC procedure and no gas or aerosol leakage was observed over the entire procedure. With an injection pressure of 20 bar, granulometry showed a mean droplet diameter (D(v,0.5)) of 47 µm with a flow rate of 0.5 mL/s, and a significantly lower diameter (30 µm) when a flow rate of 0.8 mL/s was used. Experiments using IP injection of SKOV-3 luciferase positive cells showed that after IP injection of 20 × 106 cells, miliary PM was observed in all animals. PIPAC was feasible and well supported in these tumor bearing animals. CONCLUSIONS: we propose a reproducible and efficient rodent model to study PIPAC and ePIPAC in OC xenografts with widespread PM. This model allows to characterize and optimize pharmacokinetic and biophysical parameters, and to evaluate the anti-cancer efficacy of (e)PIPAC treatment.


Assuntos
Antineoplásicos/administração & dosagem , Laparoscopia/métodos , Neoplasias Ovarianas/terapia , Neoplasias Peritoneais/terapia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Aerossóis/administração & dosagem , Animais , Linhagem Celular Tumoral , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Feminino , Humanos , Injeções Intraperitoneais/efeitos adversos , Injeções Intraperitoneais/métodos , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Peritônio/efeitos dos fármacos , Peritônio/patologia , Pressão , Ratos , Ratos Nus , Ratos Wistar , Eletricidade Estática
18.
Eur J Pharm Sci ; 136: 104938, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132401

RESUMO

Savolitinib is a novel small-molecule selective cMet inhibitor. This work characterized its pharmacokinetics in preclinical phase, established the preclinical relationships between PK, cMet modulation and anti-tumor efficacy. In vitro and in vivo animal studies were performed for PK characterization. Savolitinib showed good absorption, moderate tissue distribution, low to intermediate clearance, and low accumulation. Hepatic oxidative metabolism followed by urinary and biliary excretions was the major elimination pathway. Based on preclinical PK data, human PK profiles were predicted using empirical methods. Pharmacodynamic studies for evaluating cMet inhibition and anti-tumor efficacy were conducted in nude mice bearing Hs746t xenograft. PK/PD models were built to link the PD measurements to nude mouse PK. The established integrated preclinical PK/PD model contained a two-compartment non-linear PK model, a biomarker link model and a tumor growth transit model. The IC50 of cMet inhibition and the concentration achieving half of the maximal Hs746t tumor reduction by savolitinib were equal to 12.5 and 3.7 nM (free drug), respectively. Based on the predicted human PK data, as well as the established PK/PD model in nude mouse, the human PD (cMet inhibition) profiles were also simulated. This research supported clinical development of savolitinib. Understanding the preclinical PK/PD relationship of savolitinib provides translational insights into the cMet-targeted drug development.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/farmacologia , Pirazinas/farmacocinética , Triazinas/farmacologia , Triazinas/farmacocinética , Animais , Células CACO-2 , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Modelos Biológicos , Proteínas Proto-Oncogênicas c-met/metabolismo , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
19.
BMC Biotechnol ; 19(1): 28, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118070

RESUMO

BACKGROUND: In vivo use of monoclonal antibodies has become routine clinical practice in the treatment of human cancer. CD38 is an attractive target, because it has double roles, as a receptor and an ectoenzyme. Daratumumab, an anti-CD38 antibody, is currently in the clinical trials for multiple myeloma. RESULTS: Here we obtained a humanized anti-CD38 antibody, SG003, using SDR-grafting method. SG003 possessed stronger antigen binding activity than Daratumumab, and its epitope was far from that of Daratumumab, an anti-CD38 antibody currently in the clinical trials for multiple myeloma; besides, SG003 showed enhanced antibody-dependent cell-mediated cytotoxicity function and in vivo inhibitory efficacy of tumor growth in xenograft mice model. CONCLUSION: SG003 seemed to be a good option to improve the curative effect of CD38-related cancers.


Assuntos
ADP-Ribosil Ciclase 1/imunologia , Anticorpos Monoclonais/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Linfoma/tratamento farmacológico , ADP-Ribosil Ciclase 1/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Linhagem Celular Tumoral , Epitopos/imunologia , Epitopos/metabolismo , Humanos , Linfoma/imunologia , Linfoma/metabolismo , Camundongos SCID , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
20.
Int J Cancer ; 145(12): 3334-3346, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31081930

RESUMO

Akt is a promising therapeutic target for cancer treatment. In our study, we have identified that 7-deoxynarciclasine (7-DONCS) is a potential inhibitor of Akt, which results in the repression of multiple oncogenic processes in hepatocellular carcinoma (HCC). We have found that 7-DONCS suppresses the growth of HCC by inducing the apoptotic and autophagic capacities, as well as by inhibiting epithelial-mesenchymal transition (EMT) in vitro and in vivo. Pretreatment of cells with specific autophagy inhibitor (Bafilomycin A1) or knockdown of endogenous LC-3B by siRNA strongly abrogates 7-DONCS-regulated apoptosis and EMT. Consequently, we have found that 7-DONCS selectively inhibits phospho-Akt (Ser473), and subsequent molecular docking reveals that 7-DONCS directly binds to the C-terminal domain of Akt. Overexpressing Akt significantly blocks these effects via 7-DONCS in HCC cells. Furthermore, 7-DONCS, by targeting Akt, exhibits a promising therapeutic effect in orthotopic hepatocellular tumors. Finally, higher p-Akt expression is associated with poor prognosis, and higher level of Akt was positively correlated with the enrichment of both apoptosis and autophagy downregulation, and EMT upregulation in HCC patients. These studies suggest that 7-DONCS serves as an attractive drug candidate by targeting Akt for future HCC therapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Isoquinolinas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Simulação de Acoplamento Molecular/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
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