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1.
Life Sci ; 241: 117161, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837329

RESUMO

AIMS: Acute myeloid leukemia (AML) is an aggressive cancer that invariably produces drug resistance after treatment. The aim is to explore the role of lncRNA potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1 (KCNQ1OT1) and associated novel mechanisms in the progression and chemoresistance of AML. MAIN METHODS: The expression of KCNQ1OT1, miR-193a-3p, and Tspan3 was measured by qRT-PCR. The values of IC50 for adriamycin (ADR) and the ability of proliferation were analyzed by CCK-8 assay. Cell migration and invasion were assessed by transwell assay. Cell apoptosis was monitored by flow cytometry assay. The expression of Tspan3, MRP1, P-gp and LRP at the protein level was quantified by western blot. The relationship between miR-193a-3p and KCNQ1OT1 or Tspan3 was predicted by bioinformatics tool Diana and verified by dual-luciferase reporter assay, RIP assay or RNA pull-down assay. KEY FINDINGS: KCNQ1OT1 and Tspan3 were up-regulated, while miR-193a-3p was down-regulated in ADR resistant AML samples and cells. KCNQ1OT1 knockdown reduced ADR resistance, inhibited proliferation, migration and invasion but promoted apoptosis of ADR resistant AML cells, miR-193a-3p inhibition reversed these effects. MiR-193a-3p was a target of KCNQ1OT1 and combined with Tspan3 3' untranslated region (3' UTR). Enrichment of miR-193a-3p decreased ADR resistance, inhibited proliferation, migration and invasion and stimulated apoptosis in ADR resistant AML cells, but Tspan3 overexpression overturned these impacts. SIGNIFICANCE: KCNQ1OT1 aggravates AML progression and chemoresistance to ADR by inducing Tspan3 expression via adsorbing miR-193a-3p in ADR resistant AML cells, providing a theoretical basis for the treatment of AML with chemoresistance.


Assuntos
Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/patologia , MicroRNAs/genética , Tetraspaninas/metabolismo , Antibióticos Antineoplásicos/farmacologia , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Progressão da Doença , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Tetraspaninas/genética , Células Tumorais Cultivadas
2.
J Environ Pathol Toxicol Oncol ; 38(2): 153-163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679278

RESUMO

Chemobrain is a significant post-chemotherapy complication for which no approved treatments are available. We had previously identified that rutin inhibits doxorubicin (Dox-) -induced cognitive decline in healthy rats. However, it was important to also establish that it does so in rats with mammary carcinoma without compromising Dox's antitumor potential. Mammary carcinoma was induced in female rats by intraperitonial administration of N-methyl-N-nitrosourea (i.p.). Rats that developed mammary carcinoma were treated with Dox after pretreatment with vehicle or rutin. After Dox exposure (50 days), episodic and spatial memory was assessed using the novel object recognition task and the Morris water maze, respectively. Tumor progression was evaluated by measurement of tumor weight and volume and histological analysis. Blood samples were collected to estimate hematological parameters. Oxidative status and TNF-α levels were estimated in brain homogenates. Dox treatment significantly reduced tumor size and volume. Pretreatment with rutin did not significantly alter Dox's tumor suppression potential, suggesting that it does not influence Dox's anticancer activity. In addition, rutin ameliorated Dox-induced cognitive decline, myelosuppression, and brain oxidative stress. The present study indicates that rutin protects against Dox-induced cognitive decline and myelosuppression without affecting its antitumor potential.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/induzido quimicamente , Doxorrubicina/farmacologia , Metilnitrosoureia/toxicidade , Substâncias Protetoras/farmacologia , Rutina/farmacologia , Animais , Disfunção Cognitiva/induzido quimicamente , Doxorrubicina/toxicidade , Feminino , Ratos , Ratos Sprague-Dawley
3.
Anticancer Res ; 39(11): 6087-6095, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704836

RESUMO

BACKGROUND: RAS GTPase-activating protein-binding protein (G3BP1) is an RNA-binding protein that is essential for assembling stress granules. Many functions related to the survival and progression of cancer have been reported. The current study aimed to investigate the role of G3BP1 in radio-sensitisation of cancer cells. MATERIALS AND METHODS: Radiation sensitivity and chemosensitivity were analysed in A549 and H460 cells transfected with G3BP1 siRNAs, and N-acetyl-L-cysteine (NAC) was used to elucidate the involvement of reactive oxygen species (ROS). RESULTS: G3BP1 depletion sensitised lung cancer cell lines to radiation, and the effect was related to ROS. G3BP1 depletion impaired the intracellular ROS scavenging system and NAC abolished the radiation-sensitive phenotypes caused by G3BP1 depletion. CONCLUSION: The study suggested G3BP1 as a promising target for radio- and chemosensitisation of lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Dano ao DNA/efeitos da radiação , DNA Helicases/antagonistas & inibidores , Neoplasias Pulmonares/radioterapia , Estresse Oxidativo/efeitos da radiação , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , RNA Helicases/antagonistas & inibidores , Proteínas com Motivo de Reconhecimento de RNA/antagonistas & inibidores , Tolerância a Radiação/efeitos dos fármacos , Antibióticos Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , DNA Helicases/genética , DNA Helicases/metabolismo , Doxorrubicina/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/genética , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/genética , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas
4.
Nat Commun ; 10(1): 4731, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636264

RESUMO

Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.


Assuntos
Apoptose/efeitos dos fármacos , Glicosídeos Cardíacos/farmacologia , Senescência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Células A549 , Animais , Antibióticos Antineoplásicos/farmacologia , Bleomicina/farmacologia , Neoplasias da Mama , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Digoxina/farmacologia , Feminino , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Camundongos , Osteoartrite , Ouabaína/farmacologia , Proscilaridina/farmacologia , Fibrose Pulmonar , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Life Sci ; 238: 116938, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593704

RESUMO

AIMS: To investigate the effect of 7-O-geranylquercetin (GQ), a derivative of quercetin (Q), on reversing drug resistance in breast cancer MCF-7/ADR cells and reveal the mechanisms related to P-glycoprotein (P-gp). MAIN METHODS: Cell viability was determined by MTT assay. Accumulation of adriamycin (ADR) in cells was determined by confocal fluorescence microscope and microplate reader while that of rhodamine (Rh) was measured by flow cytometry. Expression levels of P-gp and MDR1 gene in cells were detected by western blot and Real-Time PCR, respectively. Molecular docking of GQ and Q with P-gp was conducted using AutoDock program. Xenograft model was established by inoculating MCF-7/ADR cells in BALB/c-nude mice. Tumor bearing mice were administered with ADR via tail vein injection and/or GQ (Q) by gavage. Expression levels of P-gp in tissues were detected by western blot and immunohistochemistry. KEY FINDINGS: GQ could reverse drug resistance of MCF-7/ADR cells to ADR. GQ inhibited the efflux of ADR by down-regulating the expression of P-gp protein and its encoding gene MDR1 in MCF-7/ADR cells. Molecular modeling showed that GQ matched with P-gp better than Q. GQ enhanced the antitumor effects of ADR and decreased the expression of P-gp in mice and its activities were higher than that of Q. GQ could reverse drug resistance of MCF-7/ADR cells by down-regulating the expression of P-gp in vitro and in vivo. SIGNIFICANCES: The reversal effect of GQ on P-gp-mediated drug resistance indicates its potential as a reversal agent for drug resistance in cancer chemotherapy.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Quercetina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Quercetina/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Chem Commun (Camb) ; 55(87): 13082-13084, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31608901

RESUMO

Herein, a photoelectrochemical biosensor was successfully constructed on the basis of a sensitization strategy of doxorubicin sensitized graphitic carbon nitride for the ultrasensitive detection of microRNA-141 with the assistance of a target-activated enzyme-free DNA walker.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Técnicas Biossensoriais , DNA/efeitos dos fármacos , Doxorrubicina/farmacologia , Técnicas Eletroquímicas , Grafite/química , MicroRNAs/análise , Compostos de Nitrogênio/química , Antibióticos Antineoplásicos/química , Doxorrubicina/química , Processos Fotoquímicos
9.
Can J Vet Res ; 83(4): 279-284, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31571728

RESUMO

A lack of understanding of specific immune defects underlying canine immune-mediated diseases hampers optimal therapy. Failure to tailor treatment to an individual's immune abnormality can result in lack of efficacy, secondary complications, added expense, and drug-potentiated adverse effects. We adopted a small-volume whole-blood flow cytometric assay to determine the effect of immunosuppressant drugs on T-lymphocyte proliferation. Using healthy dogs in this proof-of-principle study, we hypothesized that there would be dose-dependent suppression of T-lymphocyte proliferation in response to dexamethasone, cyclosporine, mycophenolic acid, and the active metabolite of leflunomide (A77 1726). Whole blood was collected from 6 healthy pet dogs and incubated for 4 d with or without the mitogens concanavalin A and lipopolysaccharide and with increasing concentrations of immunosuppressant. Samples were subsequently stained with viability dye and with antibodies against the pan-T-lymphocyte marker CD5 and the cell proliferation marker Ki67. Percentages of proliferating T-lymphocytes were determined by flow cytometry, and the 50% inhibitory concentration (IC50) was calculated. Inhibition of T-lymphocyte proliferation by the panel of immunosuppressants was shown to be dose-dependent, with marked variability among the dogs. The mean IC50 was 394.8 ± 871 (standard deviation) µM for dexamethasone, 18.89 ± 36.2 ng/mL for cyclosporine, 106.3 ± 157.7 nM for mycophenolic acid, and 3.746 ± 6.8 µM for A77 1726. These results support the use of this assay for detecting the efficacy of individual immunosuppressants used to diminish T-lymphocyte proliferation. In future, the assay may be applied to pet dogs with spontaneous immune-mediated disease to help tailor individual treatment.


Assuntos
Ciclosporina/farmacologia , Dexametasona/farmacologia , Cães , Leflunomida/metabolismo , Ácido Micofenólico/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Anti-Inflamatórios , Antibióticos Antineoplásicos/farmacologia , Antígenos CD5/genética , Antígenos CD5/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Imunossupressores/farmacologia , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Leflunomida/química , Leflunomida/farmacologia , Linfócitos T/fisiologia
10.
Chem Commun (Camb) ; 55(82): 12344-12347, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31556881

RESUMO

Human ferritin has been explored as a potential drug nanocarrier, but extreme conditions (pH ≤ 2.0) are required for the encapsulation of drugs. Here, by engineering the AB loop of ferritin, we obtained a new ferritin variant with no new pores, which can disassemble at pH 3.0 or 4.0 and reassemble at pH 7.0. Consequently, under mild conditions, drugs can be encapsulated within this new ferritin nanocage.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Ferritinas/química , Nanopartículas/química , Engenharia de Proteínas , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Portadores de Fármacos/química , Humanos , Concentração de Íons de Hidrogênio , Modelos Moleculares , Estrutura Secundária de Proteína
11.
Adv Mater ; 31(44): e1904278, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31549774

RESUMO

Tumor-associated enzyme-activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the paucity of tumor-associated enzymes which are essential for prodrug activation usually limits the antitumor potency. A cooperative strategy that utilizes combretastatin A4 nanodrug (CA4-NPs) and matrix metalloproteinase 9 (MMP9)-activated doxorubicin prodrug (MMP9-DOX-NPs) is developed. CA4 is a typical vascular disrupting agent that can selectively disrupt immature tumor blood vessels and exacerbate the tumor hypoxia state. After treatment with CA4-NPs, MMP9 expression can be significantly enhanced by 5.6-fold in treated tumors, which further boosts tumor-selective active drug release of MMP9-DOX-NPs by 3.7-fold in an orthotopic 4T1 mammary adenocarcinoma mouse model. The sequential delivery of CA4-NPs and MMP9-DOX-NPs exhibits enhanced antitumor efficacy with reduced systemic toxicity compared with the noncooperative controls.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Nanopartículas/química , Pró-Fármacos/farmacologia , Estilbenos/química , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular , Preparações de Ação Retardada , Doxorrubicina/química , Liberação Controlada de Fármacos , Feminino , Ácido Glutâmico/análogos & derivados , Ácido Glutâmico/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Fenilalanina/análogos & derivados , Fenilalanina/química , Polietilenoglicóis/química , Pró-Fármacos/química , Distribuição Tecidual
12.
Molecules ; 24(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31489879

RESUMO

To increase treatment efficiency for glioblastoma, we have developed a system to selectively deliver chemotherapeutic doxorubicin (Dox) to Glioblastoma (GBM) tumors. This carrier is based on elastin-like polypeptide (ELP), which is soluble at physiological temperatures but undergoes a phase transition and accumulates at tumor sites with externally applied, mild (40-41 °C) hyperthermia. The CPP-ELP-Dox conjugate consists of a cell penetrating peptide (CPP), which facilitates transcytosis through the blood brain barrier and cell entry, and a 6-maleimidocaproyl hydrazone derivative of doxorubicin at the C-terminus of ELP. The acid-sensitive hydrazone linker ensures release of Dox in the lysosomes/endosomes after cellular uptake of the drug conjugate. We have shown that CPP-ELP-Dox effectively inhibits cell proliferation in three GBM cell lines. Both the free drug and CPP-ELP-Dox conjugate exhibited similar in vitro cytotoxicity, although their subcellular localization was considerably different. The Dox conjugate was mainly dispersed in the cytoplasm, while free drug had partial nuclear accumulation in addition to cytoplasmic distribution. The intracellular Dox concentration was increased in the CPP-ELP-Dox cells compared to that in the cells treated with free Dox, which positively correlates with cytotoxic activity. In summary, our findings demonstrate that CPP-ELP-Dox effectively kills GBM cells. Development of such a drug carrier has the potential to greatly improve current therapeutic approaches for GBM by increasing the specificity and efficacy of treatment and reducing cytotoxicity in normal tissues.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Doxorrubicina/farmacologia , Elastina/química , Glioblastoma/metabolismo , Antibióticos Antineoplásicos/química , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Citoplasma/metabolismo , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Humanos , Estrutura Molecular , Solubilidade
13.
Cancer Invest ; 37(8): 339-354, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31412717

RESUMO

Squamous cell carcinoma (SCC) of skin has no standard treatment regimen, resulting in recurrences/metastasis. Although, doxorubicin (Dox), an anthracycline antibiotic has demonstrated some degree of efficacy. Molecular imaging can help in assessment of treatment response and prognosis of SCCs. MRI data showed that spin-spin relaxation (T2) time was longer (138 ± 2 msec) in Dox treated Test-II and there is no significant difference in spin-lattice relaxation (T1) time with respective controls. These findings further corroborated with the histology, proliferation index, apoptotic index, and HMGA1 protein expression. Thus, MRI may be a useful tool for monitoring treatment response noninvasively for skin tumor prognosis.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Doxorrubicina/farmacologia , Imagem por Ressonância Magnética , Imagem Molecular/métodos , Neoplasias Cutâneas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas HMGA/genética , Proteínas HMGA/metabolismo , Camundongos , Valor Preditivo dos Testes , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos
14.
Chem Commun (Camb) ; 55(72): 10654-10664, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31418758

RESUMO

Some host-guest complexes of cucurbit[n]uril (CB[n]) host molecules act as supramolecular amphiphiles (SAs), which hierarchically self-assemble into various nanomaterials such as vesicles, micelles, nanorods, and nanosheets in water. The structures and functions of the nanomaterials can be controlled by supramolecular engineering of the host-guest complexes. In addition, functionalization at the periphery of CB[6] and CB[7] generates CB[n]-based molecular amphiphiles (MAs) that can also self-assemble into vesicles or micelle-like nanoparticles in water. Taking advantage of the molecular cavities of CBs and their strong guest recognition properties, the surface of the self-assembled nanomaterials can be easily decorated with various functional tags in a non-covalent manner. In this feature article, the two types (SAs and MAs) of CB-based amphiphiles, their self-assemblies and their applications for nanotherapeutics and theranostics are presented with future perspectives.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Doxorrubicina/farmacologia , Nanoestruturas/química , Tensoativos/farmacologia , Antibióticos Antineoplásicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Células HeLa , Humanos , Células KB , Tensoativos/química
15.
Int J Mol Sci ; 20(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430949

RESUMO

Electrochemotherapy is an efficient method for the local treatment of cutaneous and subcutaneous metastases, but its efficacy as a systemic treatment remains low. The application of gene electrotransfer (GET) to transfer DNA coding for immune system modulating molecules could allow for a systemic effect, but its applications are limited because of possible side effects, e.g., immune system overactivation and autoimmune response. In this paper, we present the simultaneous electrotransfer of bleomycin and plasmid DNA as a method to increase the systemic effect of bleomycin-based electrochemotherapy. With appropriately selected concentrations of bleomycin and plasmid DNA, it is possible to achieve efficient cell transfection while killing cells via the cytotoxic effect of bleomycin at later time points. We also show the dynamics of both cell electrotransfection and cell death after the simultaneous electrotransfer of bleomycin and plasmid DNA. Therefore, this method could have applications in achieving the transient, cell death-controlled expression of immune system activating genes while retaining efficient bleomycin mediated cell killing.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Bleomicina/farmacologia , DNA/genética , Plasmídeos/genética , Transfecção/métodos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Bleomicina/administração & dosagem , Células CHO , Morte Celular/efeitos dos fármacos , Cricetulus , DNA/administração & dosagem , Eletroporação/métodos , Expressão Gênica/efeitos dos fármacos , Plasmídeos/administração & dosagem
16.
Yonsei Med J ; 60(9): 832-841, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31433581

RESUMO

PURPOSE: Epirubicin is one of the most effective drugs against osteosarcoma. miR-1301 is involved in the occurrence and development of osteosarcoma. Whether miR-1301 is responsible for the chemosensitivity of osteosarcoma cells to epirubicin remains largely unknown. MATERIALS AND METHODS: U2OS and SAOS-2 cells were treated with various concentrations of epirubicin. Flow cytometry was employed to evaluate cell apoptotic rate. Cell proliferation was measured by Cell Counting Kit-8 assay. Western blot and quantitative real-time polymerase chain reaction were utilized to detect the expressions of B-cell lymphoma-2 (Bcl-2), Bcl-2 assaciated X protein (Bax), cleaved-caspase-3, cleaved-poly (ADP-ribose) polymerases (PARP1), TP53-regulated inhibitor of apoptosis 1 (TRIAP1), and microRNA-1301 (miR-1301). The relationship between miR-1301 and TRIAP1 was determined by luciferase reporter assay. RESULTS: Epirubicin inhibited proliferation in a dose-dependent manner, induced apoptosis, decreased the expression of Bcl-2, and increased the expressions of Bax, cleaved-caspase-3, and cleaved-PARP1 in osteosarcoma cells. miR-1301 was downregulated in U2OS and SAOS-2 cells. Importantly, epirubicin significantly increased the levels of miR-1301. Overexpression of miR-1301 suppressed proliferation and promoted apoptosis. Interestingly, those effects were enhanced by epirubicin. In contrast, miR-1301 depletion attenuated the epirubicin-mediated anti-osteosarcoma effect. miR-1301 negatively regulated the expression of TRIAP1 in U2OS and SAOS-2 cells. Furthermore, epirubicin inhibited the mRNA and protein levels of TRIAP1 by upregulating miR-1301 levels. Epirubicin suppressed cell proliferation by downregulating TRIAP1. CONCLUSION: miR-1301 was implicated in the chemosensitivity of osteosarcoma to epirubicin by modulating TRIAP1.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Epirubicina/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Caspase 3/biossíntese , Linhagem Celular Tumoral , Regulação para Baixo , Epirubicina/farmacologia , Citometria de Fluxo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MicroRNAs/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
17.
J Biochem Mol Toxicol ; 33(10): e22384, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468665

RESUMO

This study aimed to investigate the effect of curcumin (CUR) on doxorubicin (DOX)-induced testicular damage in male rats. Thirty-five adult male Wistar rats were used. Control group was received saline for 7 days. CUR group received CUR for 7 days. DOX group received single dose DOX on the 5th day. DOX+ CUR-100 group received 100 mg/kg/day CUR for 7 days and DOX injection on the 5th day. DOX + CUR-200 group received 200 mg/kg/day CUR for 7 days and DOX injection on the 5th day. DOX treatment decreased in sperm motility rate, live sperm percentages, cellular antioxidants, and increased malondialdehyde (MDA) levels, necrosis, degenerations, and slimming in seminiferous tubules, and DNA damages in testes by inducing oxidative stress. CUR treatment mitigated significantly these side effects when compared with DOX group in a dose-dependent manner. In conclusion, CUR treatment can be used in the mitigation of DOX-induced testicular toxicity.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Curcumina/farmacologia , Doxorrubicina/farmacologia , Cuidados Paliativos , Testículo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Testículo/metabolismo
18.
Eur J Med Chem ; 180: 350-366, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325783

RESUMO

Overexpression of P-glycoprotein (P-gp) is one of the major causes for multidrug resistance (MDR), which has become a major obstacle in cancer therapy. One hopeful approach to reverse the MDR is to develop inhibitors of P-gp in expression and/or function. Here, we designed and synthesized a series of chalcone derivatives as P-gp inhibitors and evaluated their potential reversal activities against MDR. Among them, the most active compound MY3 had little intrinsic cytotoxicity and showed the highest activity (RF = 50.19) in reversing DOX resistance in MCF-7/DOX cells. Further studies demonstrated that MY3 could increase intracellular accumulation of DOX and inhibit expression of P-gp at mRNA and protein levels. More importantly, MY3 significantly enhanced the efficacy of DOX against the tumor xenografts bearing MCF-7/DOX cells with the precondition of unchanged body weight. Therefore, MY3 might represent a promising lead to develop MDR reversal agents for cancer chemotherapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Chalconas/farmacologia , Desenho de Drogas , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Chalconas/síntese química , Chalconas/química , Relação Dose-Resposta a Droga , Doxorrubicina/química , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células MCF-7 , Estrutura Molecular , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade
19.
Pharm Dev Technol ; 24(9): 1125-1132, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31305197

RESUMO

Clinically, co-delivery of chemotherapeutics has been limited by poor water-solubility and severe systemic toxicity. This study was aimed at integrating the merits of combination chemotherapy and mixed micellar technology and demonstrating the anticancer potential of doxorubicin (DOX) and dihydroartemisinin (DHA) co-loaded Soluplus®-TPGS mixed micellar system. In this study, physiochemically stable multidrug loaded mixed micelles were successfully prepared, encapsulation efficiencies of DOX and DHA were as high as 90%, and the average diameter of the micelles was 64.27 nm. The cellular uptake of DOX from the mixed micelles increased by 1.3 and 1.2 times for MCF-7 and MCF-7/ADR cell lines, respectively. The micelles were more cytotoxic than free DHA-DOX. Surprisingly, the co-loaded mixed micelles exhibited higher antitumor activity, while the systemic toxicity was reduced during the treatment. Therefore, the DOX and DHA mixed micelle might be a potential, effective, and less toxic drug-delivery system for cancer therapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Doxorrubicina/administração & dosagem , Polietilenoglicóis/química , Polivinil/química , Vitamina E/química , Antibióticos Antineoplásicos/farmacologia , Antimaláricos/farmacologia , Artemisininas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Combinação de Medicamentos , Feminino , Humanos , Células MCF-7 , Micelas
20.
Int J Oncol ; 55(2): 451-461, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268161

RESUMO

Gastric cancer (GC) is one of the most common cancers worldwide and results in the second greatest rate of cancer­associated mortality globally. Multidrug resistance (MDR) often develops during the chemotherapy, resulting in the failure of treatment. To investigate the molecular mechanism of MDR, the roles of microRNA (miR)­1 were studied in GC. Reverse transcription­quantitative polymerase chain reaction and western blotting were used to investigate the expression levels of miR­1 and sorcin in SGC7901/ADM and SGC7901/VCR cell lines. The effect of miR­1 on the half maximal inhibitory concentration (IC50), cell apoptosis rates and drug accumulation was uncovered by MTT assay and flow cytometric analysis. Furthermore, dual­luciferase assay and western blotting were used to determine the target of miR­1 in GC. It was demonstrated that miR­1 was highly downregulated in MDR GC cell lines, including SGC7901/ADM and SGC7901/VCR. Overexpression of miR­1 in MDR GC cells decreased IC50, but increased the cell apoptosis rates and promoted the drug accumulation in cancer cells. Dual­luciferase activity assay indicated that sorcin was the target of miR­1 in GC. In addition, overexpression of sorcin could partially reverse the effect of miR­1 in MDR GC cells. The role of miR­1 in MDR GC cells makes it a potential therapeutic target for a successful clinical outcome.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Células Tumorais Cultivadas , Vincristina/farmacologia
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