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1.
Anticancer Res ; 40(9): 4857-4867, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878773

RESUMO

BACKGROUND/AIM: Anticancer peptide PNC-27 binds to HDM-2 protein on cancer cell membranes inducing the formation of cytotoxic transmembrane pores. Herein, we investigated HDM-2 membrane expression and the effect of PNC-27 treatment on human non-stem cell acute myelogenous leukemia cell lines: U937, acute monocytic leukemia; OCI-AML3, acute myelomonocytic leukemia and HL60, acute promyelocytic leukemia. MATERIALS AND METHODS: We measured cell surface membrane expression of HDM-2 using flow cytometry. Cell viability was assessed using MTT assay while direct cytotoxicity was measured by lactate dehydrogenase (LDH) release and induction of apoptotic markers annexin V and caspase-3. RESULTS: HDM-2 is expressed at high levels in membranes of U937, OCI-AML3 and HL-60 cells. PNC-27 can bind to membrane HDM-2 to induce cell necrosis and LDH release within 4 h. CONCLUSION: Targeting membrane HDM-2 can be a potential strategy to treat leukemia. PNC-27 targeting membrane HDM-2 demonstrated significant anti-leukemia activity in a variety of leukemic cell lines.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/farmacologia , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , L-Lactato Desidrogenase/metabolismo , Leucemia Mieloide/metabolismo , Necrose , Proteína Supressora de Tumor p53/metabolismo
2.
Int J Nanomedicine ; 15: 4793-4810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764921

RESUMO

Background: Platinum resistance is a major challenge in the management of ovarian cancer. Even low levels of acquired resistance at the cellular level lead to impaired response to cisplatin. In ovarian cancer intraperitoneal therapy, nanoparticle formulation can improve the cisplatin's pharmacokinetics and safety profile. Purpose: This work aimed to investigate the chemo-sensitivity of ovarian cancer SKOV3 cells upon short-term (72h) single treatment of cisplatin and cisplatin-loaded biodegradable nanoparticles (Cis-NP). The aim was then to determine the therapeutic properties of Cis-NP in vivo using a SKOV3-luc cells' xenograft model in mice. Methods: Cell cytotoxicity was assessed after the exposure of the cell culture to cisplatin or Cis-NP. The effect of treatments on EMT and CSC-like phenotype was studied by analyzing a panel of markers by flow cytometry. Intracellular platinum concentration was determined by inductively coupled plasma mass spectrometry (ICS-MS), and gene expression was evaluated by RNAseq analysis. The efficacy of intraperitoneal chemotherapy was evaluated in a SKOV3-luc cells' xenograft model in mice, through a combination of bioluminescence imaging, histological, and immunohistochemical analyses. Results: We observed in vitro that short-term treatment of cisplatin has a critical role in determining the potential induction of chemoresistance, and a nanotechnology-based drug delivery system can modulate it. The RNAseq analysis underlines a protective effect of nanoparticle system according to their ability to down-regulate several genes involved in chemoresistance, cell proliferation, and apoptosis. The highest intracellular platinum concentration obtained with Cis-NP treatment significantly improved the efficacy. Consistent with in vitro results, we found that Cis-NP treatment in vivo can significantly reduce tumor burden and aggressiveness compared to the free drug. Conclusion: Nanoparticle-mediated cisplatin delivery may serve as an intracellular depot impacting the cisplatin pharmacodynamic performance at cellular levels. These features may contribute to improving the drawbacks of conventional intraperitoneal therapy, and therefore will require further investigations in vivo.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Portadores de Fármacos/química , Espaço Intracelular/metabolismo , Nanomedicina/métodos , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/metabolismo , Cisplatino/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Adv Exp Med Biol ; 1207: 709-724, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671788

RESUMO

Anti-cancer effect of natural products has been widely known. As a sort of multi-target anti-cancer agents, natural compound's regulation on autophagy in cancer cells has been studied as a promising research to reveal the mechanism in oncogenesis, as well as a potential short way to anti-cancer drug discovery. In this chapter, we reviewed the cancer-autophagic-related studies on several natural product compounds. It was concluded that natural product compounds directly or indirectly regulated most of the target proteins on the autophagic signal pathways. Considering we have not seen the whole clear atlas of autophagy in oncogenesis yet, it is hard to raise up any conclusion that autophagy is always playing a positive role in oncogenesis and cancer progression.


Assuntos
Autofagia , Produtos Biológicos/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos
4.
Int J Nanomedicine ; 15: 4607-4623, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32636621

RESUMO

Aim: The interaction of NPs with biological systems may reveal useful details about their pharmacodynamic, anticancer and antibacterial effects. Methods: Herein, the interaction of as-synthesized Co3O4 NPs with HSA was explored by different kinds of fluorescence and CD spectroscopic methods, as well as molecular docking studies. Also, the anticancer effect of Co3O4 NPs against leukemia K562 cells was investigated by MTT, LDH, caspase, real-time PCR, ROS, cell cycle, and apoptosis assays. Afterwards, the antibacterial effects of Co3O4 NPs against three pathogenic bacteria were disclosed by antibacterial assays. Results: Different characterization methods such as TEM, DLS, zeta potential and XRD studies proved that fabricated Co3O4 NPs by sol-gel method have a diameter of around 50 nm, hydrodynamic radius of 177 nm with a charge distribution of -33.04 mV and a well-defined crystalline phase. Intrinsic, extrinsic, and synchronous fluorescence as well as CD studies, respectively, showed that the HSA undergoes some fluorescence quenching, minor conformational changes, microenvironmental changes as well as no structural changes in the secondary structure, after interaction with Co3O4 NPs. Molecular docking results also verified that the spherical clusters with a dimension of 1.5 nm exhibit the most binding energy with HSA molecules. Anticancer assays demonstrated that Co3O4 NPs can selectively lead to the reduction of K562 cell viability through the cell membrane damage, activation of caspase-9, -8 and -3, elevation of Bax/Bcl-2 mRNA ratio, ROS production, cell cycle arrest, and apoptosis. Finally, antibacterial assays disclosed that Co3O4 NPs can stimulate a promising antibacterial effect against pathogenic bacteria. Conclusion: In general, these observations can provide useful information for the early stages of nanomaterial applications in therapeutic platforms.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Cobalto/química , Cobalto/farmacologia , Nanopartículas Metálicas/química , Óxidos/química , Óxidos/farmacologia , Albumina Sérica Humana/metabolismo , Antibacterianos/química , Antibacterianos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cobalto/metabolismo , Escherichia coli/efeitos dos fármacos , Humanos , Células K562 , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Óxidos/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Albumina Sérica Humana/química , Staphylococcus aureus/efeitos dos fármacos , Difração de Raios X
5.
Cell Prolif ; 53(8): e12858, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32592435

RESUMO

OBJECTIVES: Traditional cancer therapy and regular immunotherapy are ineffective for treating triple-negative breast cancer (TNBC) patients. Recently, chimeric antigen receptor-engineered natural killer cells (CAR NK) have been applied to target several hormone receptors on different cancer cells to improve the efficacy of immunotherapy. Furthermore, epidermal growth factor receptor (EGFR) is a potential therapeutic target for TNBC. Here, we demonstrated that EGFR-specific CAR NK cells (EGFR-CAR NK cells) could be potentially used to treat patients with TNBC exhibiting enhanced EGFR expression. MATERIALS AND METHODS: We investigated the cytotoxic effects of EGFR-CAR NK cells against TNBC cells in vitro and in vivo. The two types of EGFR-CAR NK cells were generated by transducing lentiviral vectors containing DNA sequences encoding the single-chain variable fragment (scFv) regions of the two anti-EGFR antibodies. The cytotoxic and anti-tumor effects of the two cell types were examined by performing cytokine release and cytotoxicity assays in vitro, and tumor growth assays in breast cancer cell line-derived xenograft (CLDX) and patient-derived xenograft (PDX) mouse models. RESULTS: Both EGFR-CAR NK cell types were activated by TNBC cells exhibiting upregulated EGFR expression and specifically triggered the lysis of the TNBC cells in vitro. Furthermore, the two EGFR-CAR NK cell types inhibited CLDX and PDX tumors in mice. CONCLUSIONS: This study suggested that treatment with EGFR-CAR NK cells could be a promising strategy for TNBC patients.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/metabolismo , Células Matadoras Naturais/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/imunologia , Humanos , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
6.
Chem Biol Interact ; 327: 109186, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32590071

RESUMO

In this study, we scrutinized the anticancer effects of FB-15 on human gastric carcinoma MGC-803 cells in vitro and vivo, and its preliminary effect on tubulin and HIF-1α. We confirmed that FB-15 not only inhibited the proliferation of a large number of cells in a concentration and time-dependent manner but also inhibited proliferation of a single cell to form clones. FB-15 manifested little cytotoxicity for normal stomach cells GES-1. The flow cytometry analysis displayed that FB-15 induced apoptosis MGC-803 cells and mainly arrested cells in the S phase in a concentration-dependent manner. The results of the wound healing assay indicated that FB-15 suppressed cell migration. Furthermore, the western blotting showed that FB-15 down-regulated the expression of ß3-tubulin and HIF-1α, consistent with Immunohistochemical assay. The binding modes of FB-15 with tubulin were clarified by molecular docking. FB-15 significantly suppressed the growth of MGC-803 gastric cancer tumors. The inhibitory effect of FB-15 on tumor growth was superior to 5-Fu. Taken together, these results provided evidence for FB-15 to be used as an effective anticancer drug candidate for gastric cancer.


Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Flavonoides/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Flavonoides/metabolismo , Flavonoides/farmacologia , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Ligação Proteica , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Neoplasias Gástricas/patologia , Tubulina (Proteína)/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Life Sci ; 256: 117923, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522567

RESUMO

AIMS: Liver kinase B1 (LKB1) deficiency is associated with reduced expression of programmed death ligand 1 (PD-L1) and inferior clinical outcomes of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC). This study aimed to investigate the mechanism by which LKB1 regulates PD-L1 expression and its role in programmed death 1 (PD-1) blockade therapy in NSCLC. MAIN METHODS: The impact of LKB1 on PD-L1 was assessed by western blot, qRT-PCR and immunohistochemistry in NSCLC. Activators/inhibitors of AMPK and NRF2 were applied to explore the mechanisms underlying the regulation of PD-L1 by LKB1. Efficiency of combined application of metformin and PD-1 blockade was evaluated in immunocompetent C57BL/6 mice. KEY FINDINGS: A remarkable positive correlation between LKB1 and PD-L1 expression was demonstrated in NSCLC tissues. Knockdown of LKB1 decreased PD-L1 in TC-1 cells, whereas overexpression of LKB1 increased PD-L1 in A549 cells. We further characterized that AMPK mediated the upregulation of PD-L1 by LKB1. Inhibition of AMPK or NRF2 markedly reduced PD-L1 in LKB1-intact NSCLC cells. In contrast, activation of AMPK or NRF2 reversed PD-L1 expression in LKB1-deficient NSCLC cells. Combined administration of metformin and anti-PD-1 antibody efficiently inhibited the growth of LKB1-intact tumors, whereas no obvious suppression was observed in LKB1-deficient tumors. SIGNIFICANCE: These findings demonstrated that LKB1 upregulates PD-L1 expression in NSCLC by activating the AMPK and KEAP1/NRF2 signaling. Activation of LKB1-AMPK with metformin improves the therapeutic effect of PD-1 blockade in NSCLC with wild-type LKB1.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Metformina/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Células A549 , Animais , Anticorpos Monoclonais Humanizados/metabolismo , Antineoplásicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Metformina/metabolismo , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Transdução de Sinais , Ativação Transcricional , Regulação para Cima
8.
J Biosci Bioeng ; 130(3): 265-271, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32423728

RESUMO

The efficient bioproduction of squalene-type triterpenoids (STs) has attracted considerable attention due to their significant biological activities. In a previous study, we constructed a recombinant Saccharomyces cerevisiae capable of producing three STs; 4,8-dihydroxy-22,23-oxidosqualene (ST-1), 8-hydroxy-2,3;22,23-squalene dioxide (ST-2), and 2,3;22,23-squalene dioxide (ST-3). Here, we first evaluated the effects of these STs on the growth of human non-small cell lung cancer (NSCLC) cells, and found that ST-3 exhibited the greatest potency compared to the other two STs. To further enhance the bioproduction of ST-3, we adopted a tunable system to balance the expression of the Ganoderma lucidum cytochrome P450 gene CYP505D13 in S. cerevisiae, which significantly improved the ST-3 production titer. The most effective strain produced 78.61 mg/L of ST-3 after 62 h fermentation, which was 6.43 times higher than that of our previous study. The present study demonstrated that ST-3 effectively inhibits the proliferation of NSCLC cells, and provides insight into its efficient bioproduction.


Assuntos
Biotecnologia , Sistema Enzimático do Citocromo P-450/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Esqualeno/química , Esqualeno/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fermentação , Humanos , Neoplasias Pulmonares/patologia , Esqualeno/farmacologia
9.
AAPS PharmSciTech ; 21(4): 132, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409932

RESUMO

The superiority of nanomedicine over conventional medicines in the treatment of cancer has gained immediate recognition worldwide. As traditional cancer therapies are nonspecific and detrimental to healthy cells, the ability of nanomedicine to release drugs to target tumor cells specifically instead of healthy cells has brought new hope to cancer patients. This review focuses on the effects of various factors of nanoparticles such as transport, concentration in cells, tumor microenvironment, interaction with protein, penetration, uptake by tumor cells, cancer cell mutations, and intracellular trafficking of the nanoparticle. Besides the history of nanomedicine, future perspectives of nanomedicines are also explored in this text.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanomedicina/métodos , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Humanos , Nanopartículas/química , Nanopartículas/metabolismo , Neoplasias/metabolismo , Microambiente Tumoral/fisiologia
11.
PLoS One ; 15(4): e0231633, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353864

RESUMO

Arginine deprivation cancer therapy targets certain types of malignancies with positive result in many studies and clinical trials. NEI-01 was designed as a novel arginine-depleting enzyme comprising an albumin binding domain capable of binding to human serum albumin to lengthen its half-life. In the present work, NEI-01 is shown to bind to serum albumin from various species, including mice, rat and human. Single intraperitoneal administration of NEI-01 to mice reduced plasma arginine to undetectable level for at least 9 days. Treatment of NEI-01 specifically inhibited cell viability of MIA PaCa-2 and PANC-1 cancer cell lines, which were ASS1 negative. Using a human pancreatic mouse xenograft model, NEI-01 treatment significantly reduced tumor volume and weight. Our data provides proof of principle for a cancer treatment strategy using NEI-01.


Assuntos
Antineoplásicos/uso terapêutico , Arginina/metabolismo , Carcinoma/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Desiminases de Arginina em Proteínas/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Arginina/sangue , Arginina/deficiência , Argininossuccinato Sintase/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica , Desiminases de Arginina em Proteínas/administração & dosagem , Desiminases de Arginina em Proteínas/metabolismo , Ratos , Albumina Sérica/metabolismo
12.
Nat Commun ; 11(1): 2264, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385283

RESUMO

ABCG2 is an ABC transporter that extrudes a variety of compounds from cells, and presents an obstacle in treating chemotherapy-resistant cancers. Despite recent structural insights, no anticancer drug bound to ABCG2 has been resolved, and the mechanisms of multidrug transport remain obscure. Such a gap of knowledge limits the development of novel compounds that block or evade this critical molecular pump. Here we present single-particle cryo-EM studies of ABCG2 in the apo state, and bound to the three structurally distinct chemotherapeutics. Without the binding of conformation-selective antibody fragments or inhibitors, the resting ABCG2 adopts a closed conformation. Our cryo-EM, biochemical, and functional analyses reveal the binding mode of three chemotherapeutic compounds, demonstrate how these molecules open the closed conformation of the transporter, and establish that imatinib is particularly effective in stabilizing the inward facing conformation of ABCG2. Together these studies reveal the previously unrecognized conformational cycle of ABCG2.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/ultraestrutura , Antineoplásicos/química , Transporte Biológico , Dissulfetos/metabolismo , Células HEK293 , Humanos , Mesilato de Imatinib/metabolismo , Ligantes , Mitoxantrona/química , Mitoxantrona/metabolismo , Modelos Biológicos , Estrutura Secundária de Proteína
13.
Chem Biol Interact ; 324: 109087, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32294457

RESUMO

Despite advances in cancer treatment modalities, DNA still stands as one of the targets for anticancer agents. DNA minor groove binders (MGBs) represent an important investigational chemotherapeutic class with promising cytotoxic capacity. Herein this study reports the potent cytotoxic effect of a series of repurposed flexible bis-imidamides 1-4, triaryl bis-guanidine 5 and bis-N-substituted guanidines 6,7 having a 1,4-diphenoxybenzene scaffold backbone on MCF-7 and MDA-MB-231 breast cancer cell lines. Of these compounds, imidamide 4 was chosen for further in-vitro, in-vivo and molecular dynamics (MD) studies owing to its promising anti-tumor activity, with IC50 values on MCF-7 and MDA-MB-231 breast cancer cell lines of 1.9 and 2.08 µM, respectively. Annexin V/propidium iodide apoptosis assay revealed apoptosis induction on imidamide 4 treated MCF-7 cells. RT-PCR assay results demonstrated the proapoptotic effect of compound 4 through increase of mRNA levels of the pro-apoptotic genes; p53, PUMA, and Bax, and inhibiting the anti-apoptotic Bcl-2 gene expression in MCF-7 cells. Moreover, compound 4 induced a G0/G1 cell-cycle arrest in MCF-7 in a dose-dependent manner. Corroborating in-vivo experiments on Ehrlich ascites carcinoma (EAC)-bearing mice, reflected the anticancer strength of derivative 4. For further target validation, molecular dynamics (MD) studies demonstrated an energetically favorable binding of imidamide 4 with the DNA minor groove AT rich site. In effect, imidamide 4 can be viewed as a promising hit dicationic compound with good cytotoxic and apoptotic inducing activity against breast cancer that can be adopted for future optimization.


Assuntos
Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , DNA/metabolismo , Guanidinas/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Carcinoma de Ehrlich/tratamento farmacológico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Guanidinas/química , Guanidinas/metabolismo , Humanos , Fígado/patologia , Camundongos , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade
14.
Inorg Chem ; 59(8): 5243-5246, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32255347

RESUMO

The Anderson-type hexamolybdoaluminate functionalized with lauric acid (LA), (TBA)3[Al(OH)3Mo6O18{(OCH2)3CNHCOC11H23}]·9H2O (TBA-AlMo6-LA, where TBA = tetrabutylammonium), was prepared via two synthetic routes and characterized by thermogravimetric and elemental analyses, mass spectrometry, IR and 1H NMR spectroscopy, and powder and single-crystal X-ray diffraction. The interaction of TBA-AlMo6-LA with human serum albumin (HSA) was investigated via fluorescence and circular dichroism spectroscopy. The results revealed that TBA-AlMo6-LA binds strongly to HSA (63% quenching at an HSA/TBA-AlMo6-LA ratio of 1:1), exhibiting static quenching. In contrast to TBA-AlMo6-LA, the nonfunctionalized polyoxometalate, Na3(H2O)6[Al(OH)6Mo6O18]·2H2O (AlMo6), showed weak binding toward HSA (22% quenching at a HSA/AlMo6 ratio of 1:25). HSA binding was confirmed by X-ray structure analysis of the HSA-Myr-AlMo6-LA complex (Myr = myristate). These results provide a promising lead for the design of novel polyoxometalate-based hybrids that are able to exploit HSA as a delivery vehicle to improve their pharmacokinetics and bioactivity.


Assuntos
Compostos de Alumínio/metabolismo , Ácidos Láuricos/metabolismo , Albumina Sérica Humana/metabolismo , Compostos de Alumínio/síntese química , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Dicroísmo Circular , Cristalografia por Raios X , Humanos , Ácidos Láuricos/síntese química , Molibdênio/química , Ligação Proteica , Albumina Sérica Humana/química , Espectrometria de Fluorescência , Triptofano/química
15.
J Med Chem ; 63(8): 4293-4305, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32243152

RESUMO

Acquired drug resistance in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer is a persistent challenge in cancer therapy. Previous studies of trisubstituted imidazole inhibitors led to the serendipitous discovery of inhibitors that target the drug resistant EGFR(L858R/T790M/C797S) mutant with nanomolar potencies in a reversible binding mechanism. To dissect the molecular basis for their activity, we determined the binding modes of several trisubstituted imidazole inhibitors in complex with the EGFR kinase domain with X-ray crystallography. These structures reveal that the imidazole core acts as an H-bond acceptor for the catalytic lysine (K745) in the "αC-helix out" inactive state. Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, noncovalent inhibition of the C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small-cell lung cancer.


Assuntos
Antineoplásicos/química , Variação Genética/genética , Imidazóis/antagonistas & inibidores , Mutação/genética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Cristalografia por Raios X , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Variação Genética/efeitos dos fármacos , Imidazóis/metabolismo , Mutação/efeitos dos fármacos , Estrutura Secundária de Proteína , Células Sf9
16.
Microvasc Res ; 130: 104007, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32305349

RESUMO

Magnetic nanoparticle targeting in tumor areas is examined by an integrated consideration of the transport steps from the microcirculation to the vascular walls, through their pores and into the interstitium. Brownian, flow- and magnetically induced forces and fluxes are compared on the basis of order-of-magnitude estimates and numerical simulations. The main resistance to nanoparticle transport is found to be within the interstitium, since fluxes there are much smaller than the extravasation fluxes, and the latter are much smaller than the convective-diffusive ones within the microvasculature. For typical nanoparticle sizes, magnetic properties and strengths of magnetic fields as in MRI equipment, magnetic targeting is rather unlikely to play a significant role in directing nanoparticles towards vascular walls or through vascular pores. However, magnetic drift can have an effect within the interstitium and a tangible overall outcome, despite the fact that typical magnetic forces are smaller than Brownian ones or interstitial flow convective forces. The reason behind such an effect has to do with the much larger length scales involved in interstitial transport. Magnetic drift creates a front of large nanoparticle concentrations, flooding the inadequately perfused and poorly accessible tumor area. On the basis of time-scale estimates, it is suggested that sequential cycles of magnetic nanoparticle dosage may help in more efficient access of cell layers ever closer to the tumor center. The present results may assist in the quest for optimal parameters and conditions, given the conflicting requirements for particles small enough to evade hydrodynamic and steric hindrances in vascular pores and the interstitium, yet large enough to bear a substantial magnetic load.


Assuntos
Antineoplásicos/metabolismo , Portadores de Fármacos , Magnetismo , Nanopartículas de Magnetita/química , Microvasos/metabolismo , Modelos Biológicos , Nanomedicina , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Transporte Biológico , Permeabilidade Capilar , Difusão , Composição de Medicamentos , Humanos , Hidrodinâmica , Neoplasias/tratamento farmacológico , Análise Numérica Assistida por Computador
17.
Pediatr Blood Cancer ; 67(7): e28284, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32333633

RESUMO

BACKGROUND: VTP-50469 is a potent inhibitor of the menin-MLL1 interaction and is implicated in signaling downstream of EWSR1-FLI1. PROCEDURE: VTP-50469 was evaluated against seven Ewing sarcoma (EwS) xenograft models and in vitro against EwS cell lines. RESULTS: VTP-50469 showed limited antitumor activity, statistically significantly slowing tumor progression in four tumor models but with no evidence of tumor regression. In vitro, the IC50 concentration was 10 nM for the mixed lineage leukemia (MLL)-rearranged leukemia cell line MV4;11, but > 3 µM for EwS cell lines. CONCLUSIONS: In contrast to its high level of activity against MLL1-rearranged leukemia xenografts, VTP-50469 shows little activity against EwS models.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Histona-Lisina N-Metiltransferase/efeitos dos fármacos , Proteína de Leucina Linfoide-Mieloide/efeitos dos fármacos , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Sarcoma de Ewing/tratamento farmacológico , Animais , Antineoplásicos/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Pediatria , Proteínas Proto-Oncogênicas/metabolismo , Sarcoma de Ewing/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Life Sci ; 253: 117600, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234492

RESUMO

BACKGROUND: Skin cutaneous melanoma (SKCM) is the most common subtype of skin malignancy, with ever-increasing incidence, mortality, and disease burden. Dysregulation of JAK-STATs signaling pathway is involved in the pathogenesis and progression of cancers, thus affecting the prognosis of cancer patients. The function of JAKs in SKCM is still not clarified. METHODS: A total of five online portal (GEPIA, TIMER, GeneMANIA, LinkedOmics, and GSCALite) is used to mine the expression and gene regulation network JAK2 in SKCM. RESULTS: JAK2 expression was downregulated in SKCM and significantly associated with pathological stage and the prognosis of patients. The functions of JAK2 and associated genes were primarily involved in the DNA recombination, cell cycle checkpoint, metabolic process, NOD-like receptor signaling pathways, p53 signaling pathway and apoptosis. JAK2 level was significantly correlated with the abundance of immune cells and the level of immune biomarkers. Low expression of JAK2 were resistant to QL-VIII-58, TL-1-85, Ruxolitinib, TG101348 and Sunitinib. CONCLUSIONS: Our results reveal the expression and gene regulation network of JAK2 in skin cutaneous melanoma, providing more evidences about the role of JAK2 in carcinogenesis.


Assuntos
Antineoplásicos/farmacologia , Janus Quinases/metabolismo , Melanoma/metabolismo , Pirazóis/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Sunitinibe/farmacologia , Antineoplásicos/metabolismo , Bases de Dados de Ácidos Nucleicos , Bases de Dados de Proteínas , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Janus Quinases/genética , MicroRNAs/metabolismo , Modelos Biológicos , Prognóstico , Pirazóis/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Sunitinibe/metabolismo
19.
Bull Cancer ; 107(5): 574-585, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32252973

RESUMO

Direct oral anticoagulants, anti-IIa or anti-Xa, are widely used in the treatment and prevention of venous thromboembolic disease as well as in nonvalvular atrial fibrillation. Direct oral anticoagulants are characterized by a rapid onset of activity, a predictable response and a relatively wide therapeutic window. Nevertheless, theoretical drug interactions exist since direct oral anticoagulants are substrates of the transport protein P-glycoprotein and/or of isoforms of cytochromes P450 pathway. Direct oral anticoagulants do not have a marketing authorization for the treatment of cancer-associated thrombosis unlike low-molecular-weight heparins which remain the gold standard treatment today. However, recent studies have compared low-molecular-weight heparins to direct oral anticoagulants in the treatment of cancer-associated thrombosis. Results of these studies showed a non-inferiority of direct oral anticoagulants in the prevention of recurrent thromboembolic events but at the cost of an increased hemorrhagic risk, in particular for patients with gastrointestinal and urogenital cancers. Thus, international guidelines, unlike French guidelines, integrate them in first line of the therapeutic strategy of cancer patients. We are certainly entering an era of personalized therapy for cancer-associated thrombosis, considering cancer type and also the theoretical risk of drug interactions with anti-cancer treatments or supportive care.


Assuntos
Inibidores do Fator Xa/uso terapêutico , Neoplasias/complicações , Trombose/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Anticoagulantes/uso terapêutico , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Sistema Enzimático do Citocromo P-450/metabolismo , Dabigatrana/metabolismo , Dabigatrana/uso terapêutico , Interações Medicamentosas , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/metabolismo , Hemorragia/induzido quimicamente , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Pirazóis/metabolismo , Pirazóis/uso terapêutico , Piridinas/metabolismo , Piridinas/uso terapêutico , Piridonas/metabolismo , Piridonas/uso terapêutico , Recidiva , Rivaroxabana/metabolismo , Rivaroxabana/uso terapêutico , Prevenção Secundária , Tiazóis/metabolismo , Tiazóis/uso terapêutico , Trombose/etiologia , Tromboembolia Venosa/prevenção & controle
20.
Mol Biol (Mosk) ; 54(1): 146-152, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32163398

RESUMO

Migration of cancer cells from the primary tumor site to nearby tissues is the starting point of the metastatic process. The invasive properties of cells are especially important for carcinomas, since tumor cells need to overcome the basement membrane and go beyond its boundaries to the underlying tissues. Substances that reduce the invasive ability of malignant cells are promising as antimetastatic agents. In the present work, the possibility of inhibiting the ability of different cancer cell lines to migrate under the influence of the Bacillus pumilus ribonuclease (binase) was analyzed using the scratch-wound assay. It was established that binase at non-toxic concentrations (10 µg/mL) reliably suppressed the migratory ability of HuTu 80 human duodenum adenocarcinoma cells incubated with RNase for 48-72 h. The antimetastatic potential of binase is confirmed by molecular modeling data demonstrating the ability of binase to inhibit cellular metalloproteinases that determine the migration of tumor cells.


Assuntos
Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Movimento Celular/efeitos dos fármacos , Duodeno/patologia , Ribonucleases/metabolismo , Ribonucleases/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Metaloproteases/antagonistas & inibidores , Metaloproteases/metabolismo
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