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1.
J Environ Pathol Toxicol Oncol ; 39(3): 247-260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865916

RESUMO

The anticancer activity of malvidin was studied in Dalton's lymphoma ascites (DLA)-induced solid and ascitic tumor mice models. Malvidin is a natural compound belonging to the family of O-methylated anthocyanidin and plays a predominant role in regulating both short- and long-term cellular activities. Animals were injected with DLA cells (1.5 × 106 cells/animal) to induce solid and ascitic tumors. The administration of malvidin (5 mg/kg bw and 10 mg/kg bw) was carried out for 10 consecutive days from the day of tumor induction for both solid and ascitic tumors. Cyclophosphamide, CTX (25 mg/kg bw), used as the standard drug, was also administered for 10 consecutive days. Treatment with malvidin showed a significant reduction in tumor volume and elevated white blood cell (WBC) count when compared to the DLA-bearing control animals. The treatment also maintained the body weight and hemoglobin level, and decreases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) were also noted. This investigation also reported the decreased levels of cellular glutathione (GSH) in ascitic tumor groups. Malvidin reduced inflammatory mediator and cytokine levels, such as tumor necrosis factor level alpha (TNF-α) and interleukin-6 (IL-6), which serve as molecular targets for cancer prevention. A decrease in the level of reactive oxygen species (ROS), like nitric oxide (NO), was observed. Histopathological examination revealed altered morphological changes in tumor tissue and the alleviation of hepatic architecture due to DLA. Immunohistochemical analysis revealed the inhibition of iNOS. This study demonstrated that malvidin exhibited significant in vivo antitumor activity and that it was reasonably imputable to its increasing endogenous mechanism. We accent the pertinence of malvidin as a potential naturally derived drug target for tumor control.


Assuntos
Antocianinas/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Ascite/tratamento farmacológico , Citocinas/sangue , Linfoma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antocianinas/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Ascite/metabolismo , Ascite/patologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Linfoma/metabolismo , Linfoma/patologia , Masculino , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Estresse Oxidativo/imunologia
2.
PLoS One ; 15(8): e0237098, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745124

RESUMO

The EGFR-targeting cancer therapies are commonly facing drug resistance, mostly due to mutations. Gene therapy with artificial microRNA targeting EGFR conserved sequence may avoid such problem. In this study, we constructed a recombinant adenovirus expressing EGFR-targeting artificial microRNA and active revCASP3 (Ad-EC), under the control of tumor-specific SLPI promoter, and evaluated its inhibitory effect on HEP-2 cancer cells both in vitro and in vivo. MTT assay showed that cell growth inhibition rate at 72h was 44.0% in Ad-EC group at MOI 50, while the rate was 7.7% in the control virus Ad-GFP group and 3.6% in Cetuximab (500 µg/ml) group respectively. Flow cytometry analysis revealed the late apoptotic cells rate was 36.1% in Ad-EC group, significantly higher than 6.5% of Ad-GFP group (p < 0.001). When Ad-EC (MOI 50) was combined with CDDP (0.25 µg/ml), late apoptotic cells rate increased to 61.2%, significantly higher than each monotherapy group (P < 0.001). The real-time xCELLigence system recorded an effective cell growth inhibition in Ad-EC and CDDP groups, and more enhanced effect in Ad-EC plus CDDP group. Western blot revealed that Ad-EC could inhibit the activation of AKT pathway and ERK1/2 pathway, while Cetuximab had the AKT pathway over-activated. In vivo experiments with HEP-2 xenograft in nude mice confirmed the tumor inhibition in Ad-EC, CDDP and Ad-EC plus CDDP groups compared with PBS group (P < 0.01). Collectively, these data support the effective inhibition of cancer cells by this novel gene therapy strategy.


Assuntos
Caspase 3/metabolismo , Receptores ErbB/genética , MicroRNAs/genética , Neoplasias Experimentais/terapia , Terapêutica com RNAi/métodos , Adenoviridae/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células , Cetuximab/administração & dosagem , Cetuximab/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo
3.
Proc Natl Acad Sci U S A ; 117(29): 16938-16948, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32616570

RESUMO

Despite nearly four decades of effort, broad inhibition of oncogenic RAS using small-molecule approaches has proven to be a major challenge. Here we describe the development of a pan-RAS biologic inhibitor composed of the RAS-RAP1-specific endopeptidase fused to the protein delivery machinery of diphtheria toxin. We show that this engineered chimeric toxin irreversibly cleaves and inactivates intracellular RAS at low picomolar concentrations terminating downstream signaling in receptor-bearing cells. Furthermore, we demonstrate in vivo target engagement and reduction of tumor burden in three mouse xenograft models driven by either wild-type or mutant RAS Intracellular delivery of a potent anti-RAS biologic through a receptor-mediated mechanism represents a promising approach to developing RAS therapeutics against a broad array of cancers.


Assuntos
Toxina Diftérica/metabolismo , Endopeptidases/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Proteólise , Proteínas rap1 de Ligação ao GTP/metabolismo , Proteínas ras/metabolismo , Animais , Antineoplásicos/uso terapêutico , Células Cultivadas , Toxina Diftérica/química , Toxina Diftérica/genética , Endopeptidases/química , Endopeptidases/genética , Feminino , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Nus , Mutação , Sinais Direcionadores de Proteínas , Proteínas Recombinantes/uso terapêutico , Proteínas ras/genética
4.
Life Sci ; 259: 118150, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32726663

RESUMO

Conventional therapeutic methods against cancer, including chemotherapy, radiotherapy, surgery, and combination therapy, have exhibited different toxicity levels due to their unspecific mechanism of action. To overcome the challenges facing conventional cancer therapies, newly developed methods are being investigated. Significant levels of specificity, remarkable accumulation at the tumor site, limited side effects, and minimal off-target effects enable the newly synthesized nanoparticles (NPs) to become the preferred drug delivery method in anticancer therapeutic approaches. According to the literature, CD73 has a pivotal role in cancer progression and resistance to chemotherapy and radiotherapy. Therefore, CD73 has attracted considerable attention among scientists to target this molecule. Accordingly, FDA approved CDK inhibitors such as Dinaciclib that blocks CDK1, 2, 5, and 9, and exhibits significant anticancer activity. So in this study, we intended to simultaneously suppress CD73 and CDKs in cancer cells by using the folic acid (FA)-conjugated chitosan-lactate (CL) NPs loaded with anti-CD73 siRNA and Dinaciclib to control tumor progression and metastasis. The results showed that NPs could effectively transfect cancer cells in a FA receptor-dependent manner leading to suppression of proliferation, survival, migration, and metastatic potential. Moreover, the treatment of tumor-bearing mice with this combination strategy robustly inhibited tumor growth and enhanced survival time in mice. These findings imply the high potential of FA-CL NPs loaded with anti-CD73 siRNA and Dinaciclib for use in cancer treatment shortly.


Assuntos
5'-Nucleotidase/efeitos dos fármacos , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Ácido Fólico , Nanopartículas , Compostos de Piridínio/farmacologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/farmacologia , 5'-Nucleotidase/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Terapia Combinada , Quinases Ciclina-Dependentes/efeitos dos fármacos , Progressão da Doença , Sistemas de Liberação de Medicamentos , Sinergismo Farmacológico , Humanos , Camundongos , Metástase Neoplásica/tratamento farmacológico , Neoplasias Experimentais/tratamento farmacológico , Ensaio Tumoral de Célula-Tronco
5.
Int J Nanomedicine ; 15: 3843-3850, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581534

RESUMO

Purpose: Despite tremendous results achieved by immune checkpoint inhibitors, most patients are not responders, mainly because of the lack of a pre-existing anti-tumor immune response. Thus, solutions to efficiently prime this immune response are currently under intensive investigations. Radiotherapy elicits cancer cell death, generating an antitumor-specific T cell response, turning tumors in personalized in situ vaccines, with potentially systemic effects (abscopal effect). Nonetheless, clinical evidence of sustained anti-tumor immunity as abscopal effect are rare. Methods: Hafnium oxide nanoparticles (NBTXR3) have been designed to increase energy dose deposit within cancer cells. We examined the effect of radiotherapy-activated NBTXR3 on anti-tumor immune response activation and abscopal effect production using a mouse colorectal cancer model. Results: We demonstrate that radiotherapy-activated NBTXR3 kill more cancer cells than radiotherapy alone, significantly increase immune cell infiltrates both in treated and in untreated distant tumors, generating an abscopal effect dependent on CD8+ lymphocyte T cells. Conclusion: These data show that radiotherapy-activated NBTXR3 could increase local and distant tumor control through immune system priming. Our results may have important implications for immunotherapeutic agent combination with radiotherapy.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Háfnio/farmacologia , Óxidos/farmacologia , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacocinética , Disponibilidade Biológica , Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/imunologia , Feminino , Háfnio/química , Háfnio/farmacocinética , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/radioterapia , Óxidos/química , Óxidos/farmacocinética
6.
Ultrasonics ; 108: 106198, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32590261

RESUMO

Contrast-enhanced ultrasound (CEUS) is widely applied in cancer diagnosis clinically. However, the gas-filled contrast agents are unstable in the blood and exhibit shorter imaging time, which limit their clinical use. In this study, a diagnostic nanoparticle system was developed for dual-mode imaging (ultrasound and fluorescence), which after encapsulation with doxorubicin (DOX) demonstrated simultaneous therapeutic function towards cancer treatment. Thus, calcium carbonate (CaCO3) nanoparticles were encapsulated with doxorubicin (DOX) to obtain CaCO3-DOX. Under acidic conditions, it produced carbon dioxide (CO2) to enhance ultrasound imaging and increase the release of DOX. After intravenously injecting CaCO3-DOX to tumor-bearing mice, in the presence of an ultrasound field, CO2bubbles were sufficiently generated at the tumor tissues for echogenic reflectivity. Also, the indocyanine green (ICG) was encapsulated into CaCO3 nanoparticles, to further detect the tumor with fluorescence. The resultant theranostic nanoparticle system exhibited therapeutic efficacy towards tumour-bearing mice. Overall, this investigation provides an attractive strategy for dual-mode cancer diagnostics.


Assuntos
Carbonato de Cálcio/farmacologia , Doxorrubicina/farmacologia , Imagem Multimodal , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Nanomedicina Teranóstica/métodos , Ultrassonografia/métodos , Animais , Carbonato de Cálcio/química , Dióxido de Carbono/metabolismo , Linhagem Celular Tumoral , Meios de Contraste , Doxorrubicina/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Fluorescência , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Microambiente Tumoral
7.
J Cancer Res Ther ; 16(1): 78-87, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362613

RESUMO

Aims: In the present study, the flavonoid fraction of Tabernaemontana divaricata flavonoid fraction(TdFf) leaves was investigated for its in vitro and in vivo antioxidative and antitumor activity. Subjects and Methods: The flavonoid fraction of ethyl acetate extract was assessed for their in vitro antioxidant activity by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), superoxide radicals, ferric reducing antioxidant power (FRAP), hydrogen peroxide, hydroxyl radicals and nitric oxide and in vivo antioxidative activity by enzymic and nonenzymic antioxidants in the liver of intraperitoneally implanted Ehrlich's lymphoma (EAC) and Dalton's lymphoma ascites (DLAs) model. The in vitro cytotoxicity was assessed using trypan blue exclusion assay and in vivo antitumor activity was assessed by screening the ILS, serum liver marker enzymes and histopathology of the liver. Statistical Analysis Used: The data were expressed as the mean ± standard deviation of the means, and statistical analysis was carried out employing one-way and two-way analysis of variance using Web Agri Stat Package 2.0. Results: The dose-dependent percentage scavenging of ABTS, DPPH, FRAP, OH, superoxide radical, and nonradical NO and H2O2 by TdFf indicated their antioxidative potential. Incubation of EAC/DLA tumor cells with TdFf showed a concentration-dependent cytotoxic effect, and the extract killed 50% of EAC/DLA tumor cells at a concentration of 80 µg of TdFf. Coadministration of TdFf with EAC/DLA-induced mice showed a significant increase in the liver enzymic and nonenzymic antioxidants and significant decrease in the serum liver marker enzymes to prove the in vivo antioxidative and antitumor activity of TdFf. It was also confirmed by the histopathology of the liver. Conclusions: It may be concluded that the flavonoid fractions of Td possess considerable antioxidative and antitumorigenic activity against the tested DLA/EAC in both in vitro and in vivo system.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Ascite/tratamento farmacológico , Carcinoma de Ehrlich/tratamento farmacológico , Flavonoides/farmacologia , Linfoma/tratamento farmacológico , Tabernaemontana/química , Animais , Ascite/metabolismo , Ascite/patologia , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Técnicas In Vitro , Linfoma/metabolismo , Linfoma/patologia , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Extratos Vegetais/farmacologia , Folhas de Planta/química
8.
Int J Nanomedicine ; 15: 2119-2129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32280210

RESUMO

Purpose: Chemotherapy is the primary treatment for advanced colon cancer, but its efficacy is often limited by severe toxicities. Targeted therapy in the form of selectively drug delivery system (SDDS) is an important strategy to reduce adverse effects. Here, we aim to design a novel SDDS with potential for practical application using biocompatible components and scalable production process, for targeted delivery of doxorubicin (Dox) to colon cancer cells. Methods: The SDDS was made of a self-assembled DNA nano-cross (Holliday junction, or HJ) functionalized by four AS1411 aptamers (Apt-HJ) and loaded with Dox. Results: Apt-HJ had an average size of 12.45 nm and a zeta potential of -11.6 mV. Compared with the monovalent AS1411 aptamer, the quadrivalent Apt-HJ showed stronger binding to target cancer cells (CT26). A complex of Apt-HJ and doxorubicin (Apt-HJ-Dox) was formed by intercalating Dox into the DNA structure of Apt-HJ, with each complex carrying approximately 17 Dox molecules. Confocal microscopy revealed that Apt-HJ-Dox selectively delivered Dox into CT26 colon cancer cells but not the control cells. Moreover, Apt-HJ-Dox achieved targeted killing of CT26 cancer cells in vitro and reduced the damage to control cells. Importantly, compared with free Dox, Apt-HJ-Dox significantly enhanced the antitumor efficacy in vivo without boosting the adverse effects. Conclusion: These results suggest that Apt-HJ-Dox has application potential in targeted treatment of colon cancer.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Aptâmeros de Nucleotídeos/química , Neoplasias do Colo/tratamento farmacológico , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Animais , Aptâmeros de Nucleotídeos/administração & dosagem , Células CHO , Linhagem Celular Tumoral , Cricetulus , DNA Cruciforme/química , Camundongos , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência , Nanoestruturas/química , Neoplasias Experimentais/tratamento farmacológico , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/química
9.
Int J Nanomedicine ; 15: 2315-2322, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308383

RESUMO

Purpose: In order to prepare functional Au nanoparticles with low toxicity and high antitumor properties, we have used fruit waste (banana peel) to synthesize a new dendrite-shaped gold nanoparticle and used it for the treatment of tumors. Methods: Dendrite-shaped gold nanoparticle (Au-dendrite) was synthesized through a facile hydrothermal process. The banana peel was used as both the reducing agent and the protective agent for reducing chloroauric acid to obtain Au-dendrite. The safety assessment of the Au-dendrite was conducted by H&E staining of the mouse's eyelid skin and CCK-8 assay. The antitumor effects were evaluated through in vitro tumor cytotoxicity experiments and in vivo treatment of animal tumors. Results: In this work, a new type of gold nanomaterial (Au-dendrite) was synthesized by using a common agricultural waste (banana peel) through a facile hydrothermal process without any extra chemical reducing agent or protective agent. Subsequent experiments showed that, compared with some classical Au nanomaterials, the as-synthesized gold nanocomposites have superior biocompatibility and impressive characteristics of dual inhibition toward tumor growth and migration. Conclusion: We successfully synthesized a dendrite-shaped gold nanocomposite which was derived from a common agricultural waste (banana peel). A facile and environmentally friendly synthetic process was proposed accordingly without regular chemical additives. The as-prepared Au-dendrite nanocomposites not only had better biocompatibility than some classical gold nanoparticles but also exhibited unique advantages in tumor inhibition.


Assuntos
Antineoplásicos/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Musa/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Cloretos/química , Dendritos/química , Frutas/química , Compostos de Ouro/química , Camundongos Nus , Nanocompostos/química , Neoplasias Experimentais/tratamento farmacológico
10.
Zhongguo Zhong Yao Za Zhi ; 45(2): 374-382, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237321

RESUMO

The aim of this paper was to obtain low toxicity and high efficiency anti-tumor Chinese medicine through screening the combination ratios of Momordicae Semen and Epimedii Folium, and to explore the anti-tumor mechanism of the combination of two drugs by observing their effect on apoptosis-related proteins in cancer cells. Methyl thiazolyl tetrazolium(MTT) assay was used to observe the effect of drug combination on the proliferation of tumor cells from different tissue sources. The effects of the combination of the two drugs on tumor cells were analyzed by Compusyn software. Plate cloning assay was used to observe the effect of combination of these two drugs on the proliferation of A549 cells in vitro. The expression of reactive oxygen species(ROS) and apoptotic proteins p53, Bcl-2 and Bax were compared by using ROS kit and Western blot. Lewis lung cancer model was used to observe the anti-tumor effect of drugs in vivo. The results showed that the anti-tumor effect of their ethanol extract was more significant than that of water extract, and the anti-proliferation effect was strongest when the ratio was 1∶1(P<0.05). Compusyn analysis showed that the combination of the two drugs had synergistic effect. Further studies showed that after combined use, the number of clonogen formation in A549 cells was significantly reduced(P<0.01); ROS production was increased; the expression of apoptosis-related protein p53 was up-regulated, and the ratio of Bcl-2/Bax was decreased. In vivo animal study showed that the tumor inhibition rate was 53.06%(P<0.05) in the high dose group. As compared with the single use of the two drugs, the combination of the two drugs had more significant anti-proliferative effect on tumors, and the optimum ratio was 1∶1. The combination of the two drugs at a ratio of 1∶1 inhibited the proliferation of various tumor cells, and had no significant effect on normal liver cells LO2 when compared with other ratios. Therefore, it can be preliminarily inferred that the combination of the two drugs may have the effect of synergism and detoxification. Further studies showed that the combination of the two drugs can significantly inhibit the proliferation of A549 cells, and its mechanism may be related to the activation of endogenous apoptotic pathway. In vivo experiments also showed that the tumor inhibition rate increased with the increase of drug concentration.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Epimedium/química , Neoplasias Pulmonares/tratamento farmacológico , Momordica/química , Células A549 , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Experimentais/tratamento farmacológico , Folhas de Planta/química , Sementes/química
11.
Toxicol Appl Pharmacol ; 392: 114918, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32045588

RESUMO

Orlistat (Xenical™), a US Food and Drug Administration (FDA)-approved anti-obesity drug, shows efficacy against multiple tumor types, including hepatocellular carcinoma (HCC), due to its ability to inhibit fatty acid synthase (FASN) activity. However, whether orlistat affects hepatocellular malignant transformation during hepatocarcinogenesis in vivo is unknown. This study assessed the antisteatotic and antitumorigenic efficacy of orlistat in a rapid HCC FVB/N mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes. Human hepatoma cell lines were used for mechanical validation in vitro. Hematoxylin and eosin staining, immunohistochemistry, and immunoblotting were applied for the mechanistic investigation. The results revealed that when orlistat was administered in the early stage of AKT/c-Met-triggered hepatocarcinogenesis, it resulted in the elimination of hepatic tumor burden. Mechanistically, orlistat efficiently elevated PTEN expression and suppressed AKT/SREBP1/FASN signaling both in vivo and in vitro, impairing AKT/c-Met-driven de novo lipogenesis and aberrant proliferation. Altogether, this study demonstrates the antilipogenic and antiproliferative efficacy of orlistat in hepatocarcinogenesis, suggesting that orlistat may be beneficial for the treatment of HCC, especially in NAFLD-related HCCs featuring activated AKT/mTOR cascade and increased lipogenesis in livers.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Fígado/metabolismo , Orlistate/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/farmacologia
12.
Acta Cir Bras ; 34(12): e201901207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049187

RESUMO

In the muscle invasive bladder cancer (MIBC) standard of care treatment only patients presenting a major pathological tumor response are more likely to show the established modest 5% absolute survival benefit at 5 years after cisplatin-based neoadjuvant chemotherapy (NAC). To overcome the drawbacks of a blind NAC (i.e. late cystectomy with unnecessary NAC adverse events) with potential to survival improvements, preclinical models of urothelial carcinoma have arisen in this generation as a way to pre-determine drug resistance even before therapy is targeted. The implantation of tumor specimens in the chorioallantoic membrane (MCA) of the chicken embryo results in a high-efficiency graft, thus allowing large-scale studies of patient-derived "tumor avatar". This article discusses a novel approach that exploits cancer multidrug resistance to provide personalized phenotype-based therapy utilizing the MIBC NAC dilemma.


Assuntos
Carcinoma/tratamento farmacológico , Membrana Corioalantoide , Neoplasias Experimentais/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Urotélio , Animais , Carcinoma/patologia , Membrana Corioalantoide/patologia , Humanos , Ilustração Médica , Terapia Neoadjuvante , Inoculação de Neoplasia , Neoplasias Experimentais/patologia , Fenótipo , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia
13.
Technol Cancer Res Treat ; 19: 1533033819886896, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32065066

RESUMO

BACKGROUND: Association of drugs acting against different antiangiogenic mechanisms may increase therapeutic effect and reduce resistance. Noninvasive monitoring of changes in the antiangiogenic response of individual tumors could guide selection and administration of drug combinations. Noninvasive detection of early therapeutic response during dual, vertical targeting of the vascular endothelial growth factor pathway was investigated in an ectopic subcutaneous xenograft model for human pancreatic tumor. METHODS: Dynamic contrast-enhanced ultrasound 12 MHz was used to monitor tumor-bearing Naval Medical Research Institute mice beginning 15 days after tumor implantation. Mice received therapy from 15 to 29 days with sorafenib (N = 9), ziv-aflibercept (N = 11), combined antiangiogenic agents (N = 11), and placebo control (N = 14). Sorafenib (BAY 43-9006; Nexavar), a multikinase inhibitor acting on Raf kinase and receptor tyrosine kinases-including vascular endothelial growth factor receptors 2 and 3-was administered daily (60 mg/kg, per os). Ziv-aflibercept (ZALTRAP), a high-affinity ligand trap blocking the activity of vascular endothelial growth factor A, vascular endothelial growth factor B, and placental growth factor was administered twice per week (40 mg/kg, intraperitoneally). RESULTS: Functional evaluation with dynamic contrast-enhanced ultrasound indicated stable tumor vascularization for the control group while revealing significant and sustained reduction after 1 day of therapy in the combined group (P = .007). There was no survival benefit or penalty due to drug combination. The functional progression-free survival assessed with dynamic contrast-enhanced ultrasound was significantly higher for the 3 treated groups; whereas, the progression-free survival based on tumor size did not discriminate therapeutic effect. CONCLUSIONS: Dynamic contrast-enhanced ultrasound, therefore, presents strong potential to monitor microvascular modifications during antiangiogenic therapy, a key role to monitoring antiangiogenic combining therapy to adapt dose range drug.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Meios de Contraste/administração & dosagem , Aumento da Imagem/métodos , Neoplasias Experimentais/patologia , Neovascularização Patológica/patologia , Neoplasias Pancreáticas/patologia , Ultrassonografia/métodos , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/tratamento farmacológico , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Curva ROC , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Sorafenibe/administração & dosagem , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Cancer Cell ; 37(3): 340-353.e6, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32109375

RESUMO

Inhibition of the cell-cycle kinases CDK4 and CDK6 is now part of the standard treatment in advanced breast cancer. CDK4/6 inhibitors, however, are not expected to cooperate with DNA-damaging or antimitotic chemotherapies as the former prevent cell-cycle entry, thus interfering with S-phase- or mitosis-targeting agents. Here, we report that sequential administration of CDK4/6 inhibitors after taxanes cooperates to prevent cellular proliferation in pancreatic ductal adenocarcinoma (PDAC) cells, patient-derived xenografts, and genetically engineered mice with Kras G12V and Cdkn2a-null mutations frequently observed in PDAC. This effect correlates with the repressive activity of CDK4/6 inhibitors on homologous recombination proteins required for the recovery from chromosomal damage. CDK4/6 inhibitors also prevent recovery from multiple DNA-damaging agents, suggesting broad applicability for their sequential administration after available chemotherapeutic agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Albuminas/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Reparo do DNA/efeitos dos fármacos , Esquema de Medicação , Recombinação Homóloga/efeitos dos fármacos , Humanos , Camundongos Nus , Camundongos Transgênicos , Mutação , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridinas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Chem Commun (Camb) ; 56(20): 3069-3072, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32049075

RESUMO

Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes (PtRu 1-4) have been synthesized and evaluated for their antitumor performance. Using the optimal complex, PtRu-1, we show that this water-soluble chimeric prodrug not only potently inhibits the metastasis and proliferation of tumor cells but also has an unexpectedly higher safety margin in animals compared with the traditionally-used, clinically approved drug cisplatin.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Niacina/farmacologia , Platina/farmacologia , Rutênio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Niacina/química , Platina/química , Rutênio/química , Relação Estrutura-Atividade
16.
Biomater Sci ; 8(5): 1270-1278, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32067024

RESUMO

In this research, an optimized phosphor combined with naturally green chlorophyll (Phosphor-Chlorophyll, denoted as Ph-chl) was designed for dual-modal luminescence-guided anti-tumor surgery and photodynamic therapy (PDT). A genetic algorithm (GA) is used to solve the "low up-conversion luminescence (UCL) and short-wavelength infrared (SWIR) intensity" problem by coding the proportions of elements in the phosphor in order to find the optimal phosphor with enhanced red UCL emission and SWIR luminescence using Yb/Er in the core and Yb/Nd in the shell. Moreover, when phosphors with different emission light colors (blue and green) are combined with chlorophyll as the control, the results indicate that phosphors with red emission as the energy donor have high PDT efficiency to activate the chlorophyll for reactive oxygen species (ROS) production. Additionally, due to the enhanced penetration and retention (EPR) effect, the as-synthesized Ph-chl could be used for surgery navigation with a higher SWIR imaging effect focusing on cancer rather than normal tissues and paracancerous tissue. Thus, the high dual-modal luminescence guided surgery properties of the final optimized phosphor will promote its further use in minimally-invasive endoscopic clinical surgery navigation.


Assuntos
Clorofila/química , Elementos da Série dos Lantanídeos/química , Nanocompostos/química , Neoplasias Experimentais/cirurgia , Cirurgia Assistida por Computador/métodos , Nanomedicina Teranóstica/métodos , Animais , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Imagem Multimodal/métodos , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Fotoquimioterapia/métodos
18.
Proc Natl Acad Sci U S A ; 117(3): 1321-1329, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31896586

RESUMO

Cysteine thiols of many cancer-associated proteins are attractive targets of anticancer agents. Herein, we unequivocally demonstrate a distinct thiol-targeting property of gold(III) mesoporphyrin IX dimethyl ester (AuMesoIX) and its anticancer activities. While the binding of cysteine thiols with metal complexes usually occurs via M-S bond formation, AuMesoIX is unique in that the meso-carbon atom of the porphyrin ring is activated by the gold(III) ion to undergo nucleophilic aromatic substitution with thiols. AuMesoIX was shown to modify reactive cysteine residues and inhibit the activities of anticancer protein targets including thioredoxin, peroxiredoxin, and deubiquitinases. Treatment of cancer cells with AuMesoIX resulted in the formation of gold-bound sulfur-rich protein aggregates, oxidative stress-mediated cytotoxicity, and accumulation of ubiquitinated proteins. Importantly, AuMesoIX exhibited effective antitumor activity in mice. Our study has uncovered a gold(III)-induced ligand scaffold reactivity for thiol targeting that can be exploited for anticancer applications.


Assuntos
Antineoplásicos/química , Cisteína/química , Ouro/química , Mesoporfirinas/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Enzimas Desubiquitinantes/química , Enzimas Desubiquitinantes/metabolismo , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Peroxirredoxinas/química , Peroxirredoxinas/metabolismo , Ligação Proteica , Tiorredoxinas/química , Tiorredoxinas/metabolismo , Distribuição Tecidual
19.
Pediatr Blood Cancer ; 67(5): e28098, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31975571

RESUMO

INTRODUCTION: WEE1 is a serine kinase central to the G2 checkpoint. Inhibition of WEE1 can lead to cell death by permitting cell-cycle progression despite unrepaired DNA damage. AZD1775 is a WEE1 inhibitor that is in clinical development for children and adults with cancer. METHODS: AZD1775 was tested using a dose of 120 mg/kg administered orally for days 1 to 5. Irinotecan was administered intraperitoneally at a dose of 2.5 mg/kg for days 1 to 5 (one hour after AZD1775 when used in combination). AZD1775 and irinotecan were studied alone and in combination in neuroblastoma (n = 3), osteosarcoma (n = 4), and Wilms tumor (n = 3) xenografts. RESULTS: AZD1775 as a single agent showed little activity. Irinotecan induced objective responses in two neuroblastoma lines (PRs), and two Wilms tumor models (CR and PR). The combination of AZD1775 + irinotecan-induced objective responses in two neuroblastoma lines (PR and CR) and all three Wilms tumor lines (CR and 2 PRs). The objective response measure improved compared with single-agent treatment for one neuroblastoma (PR to CR), two osteosarcoma (PD1 to PD2), and one Wilms tumor (PD2 to PR) xenograft lines. Of note, the combination yielded CR (n = 1) and PR (n = 2) in all the Wilms tumor lines. The event-free survival was significantly longer for the combination compared with single-agent irinotecan in all models tested. The magnitude of the increase was greatest in osteosarcoma and Wilms tumor xenografts. CONCLUSIONS: AZD1775 potentiates the effects of irinotecan across most of the xenograft lines tested, with effect size appearing to vary across tumor panels.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Experimentais/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Tumor de Wilms/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Criança , Feminino , Humanos , Irinotecano/farmacologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Camundongos , Camundongos SCID , Neoplasias Experimentais/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Tumor de Wilms/metabolismo , Tumor de Wilms/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Dalton Trans ; 49(5): 1613-1619, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31942585

RESUMO

We herein designed two new PtIV prodrugs of oxoplatin (cis,cis,cis-[PtCl2(NH3)2(OH)2]), [PtIVCl2(NH3)2(O2C-FA)2] (Pt-2) and [PtIVCl2(NH3)2(O2C-RH)2] (Pt-3), by conjugating with ferulic acid (FA-COOH) and rhein (RH-COOH) which have well-known biological activities. Three other Pt(iv) complexes of [PtIVCl2(NH3)2(O2C-BA)2] (Pt-1), [PtIVCl2(NH3)2(O2C-CA)2] (Pt-4) and [PtIVCl2(NH3)2(O2C-TCA)2] (Pt-5) (where BA-COOH = benzoic acid, CA-COOH = crotonic acid and TCA-COOH = trans-cinnamic acid) were also prepared for the comparative study. Like most PtIV prodrug complexes, the cytotoxicity of Pt-3 containing the biologically active rhein (RH-COOH) ligand against lung carcinoma (A549 and A549/DDP) cells was higher than those of Pt-1, Pt-2, Pt-4, cisplatin and Pt-5. Moreover, the cytotoxicity of Pt-3 in HL-7702 normal cells was lower than those of PtIV derivatives bearing BA-COOH, FA-COOH, TCA-COOH and CA-COOH ligands. The highly efficacious Pt-2 and Pt-3 were found to accumulate strongly in the A549/DDP cells, with the prodrug Pt-3 showing highest levels of penetration into the mitochondria. The prodrug Pt-3 effectively entered the A549/DDP cells and caused mitochondrial damage, significantly greater than Pt-2. In addition, the prodrug Pt-3 exhibited higher antitumor efficacy (inhibition rates (IR) = 67.45%) than Pt-2 (28.12%) and cisplatin (33.05%) in the A549/DDP xenograft mouse model. Thus, the prodrug Pt-3 containing the rhein (RH-COOH) ligand is a promising candidate drug targeting the mitochondria.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Cisplatino/análogos & derivados , Ácidos Cumáricos/farmacologia , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/farmacologia , Células A549 , Animais , Antraquinonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Ácidos Cumáricos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
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