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1.
Anticancer Res ; 39(10): 5461-5471, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570440

RESUMO

BACKGROUND/AIM: Multidrug resistance (MDR) is often associated with overexpression of P-glycoprotein (ABCB1) in cancer cells. Apatinib is a novel Vascular endothelial growth factor receptor-TKI (VEGFR-TKI) which inhibits the function of ABCB1 in certain cancers. This study aimed to investigate the effect of apatinib on the reversal of paclitaxel (PTX) resistance in A549 lung cancer cells (A549/PTX) and related mechanisms. MATERIALS AND METHODS: A549/PTX cells were treated with apatinib alone, PTX alone, or PTX and apatinib. Cell viability was measured by the CCK8 assay. Apoptosis rate, cell-cycle arrest, Rhodamine efflux and reactive oxygen species (ROS) generation were determined by flow cytometry. The intracellular paclitaxel concentration was measured by ultra performance liquid chromatography (UPLC). Protein levels were analyzed by western blotting. RESULTS: A549/PTX cells had significant resistance to PTX and higher expression of ABCB1 compared to A549 cells. Apatinib increased the cytotoxicity of PTX, enhanced PTX-induced apoptosis and cycle arrest, and triggered intracellular ROS generation in A549/PTX cells. In addition, apatinib treatment increased the concentration of intracellular PTX in A549/PTX cells. Apatinib-PTX combination inhibited AKT and ERK pathways. CONCLUSION: Apatinib reverses the drug resistance to PTX in A549 PTX-resistant cells through inhibiting the function of ABCB1 and resumes anti-cancer effects.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Piridinas/farmacologia , Células A549 , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo
2.
Pharm Res ; 36(11): 154, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482205

RESUMO

PURPOSE: Conjugation of nanocarriers with antibodies that bind to specific membrane receptors that are overexpressed in cancer cells enables targeted delivery. In the present study, we developed and synthesised two PAMAM dendrimer-trastuzumab conjugates that carried docetaxel or paclitaxel, specifically targeted to cells which overexpressed HER-2. METHODS: The 1H NMR, 13C NMR, FTIR and RP-HPLC were used to analyse the characteristics of the products and assess their purity. The toxicity of PAMAM-trastuzumab, PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined using MTT assay and compared with free trastuzumab, docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. The cellular uptake and internal localisation were studied using flow cytometry and confocal microscopy, respectively. RESULTS: The PAMAM-drug-trastuzumab conjugates in particular showed extremely high toxicity toward the HER-2-positive SKBR-3 cells and very low toxicity towards to HER-2-negative MCF-7 cells. As expected, the HER-2-positive SKBR-3 cell line accumulated trastuzumab from both conjugates rapidly; but surprisingly, although a large amount of PAMAM-ptx-trastuzumab conjugate was observed in the HER-2-negative MCF-7 cells. Confocal microscopy confirmed the intracellular localisation of analysed compounds. The key result of fluorescent imaging was the identification of strong selective binding of the PAMAM-doc-trastuzumab conjugate with HER-2-positive SKBR-3 cells only. CONCLUSIONS: Our results confirm the high selectivity of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates for HER-2-positive cells, and demonstrate the utility of trastuzumab as a targeting agent. Therefore, the analysed conjugates present an promising approach for the improvement of efficacy of targeted delivery of anticancer drugs such as docetaxel or paclitaxel.


Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Dendrímeros/química , Docetaxel/química , Paclitaxel/química , Receptor ErbB-2/metabolismo , Trastuzumab/química , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Interações de Medicamentos , Liberação Controlada de Fármacos , Corantes Fluorescentes/química , Humanos , Paclitaxel/farmacologia , Propriedades de Superfície , Trastuzumab/farmacologia , Resultado do Tratamento
3.
Int Heart J ; 60(5): 1070-1076, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31484856

RESUMO

The efficacy of drug-coated balloons (DCB) for in-stent restenosis (ISR) in hemodialysis (HD) patients remains unclear.We retrospectively evaluated 153 consecutive patients who underwent DCB for ISR with follow-ups for up to 3 years after the procedure between February 2014 and June 2017. Patients were divided into an HD group (n = 39) and a non-HD group (n = 114). The primary endpoint was target lesion revascularization (TLR). The secondary endpoints were all revascularizations and major adverse cardiac events (MACE) defined as cardiac death, myocardial infarction and cerebral infarction. Kaplan-Meier curves of survival free from TLR were compared between the two groups. We also performed propensity score matching and then compared the two matched groups (n = 27 in each group). The acute procedure success rate was similar for the two groups (100% versus 99.1%, P = 0.56). The incidence of TLR was higher in the HD group than in the non-HD group (41.0% versus 9.6%, P < 0.0001). The rate of revascularizations and MACE combined was significantly higher in the HD group than in the non-HD group (64.1% versus 17.5%, P < 0.0001). Kaplan-Meier analyses showed that survival free from TLR was significantly lower in the HD group than in the non-HD group both before and after propensity score matching (P < 0.0001 and P = 0.005, respectively; log-rank test).Contrary to the similar acute procedure success, recurrent ISR and MACE occurred more frequently in HD patients than in non-HD patients after DCB, which indicates poorer long-term efficacy of DCB in HD patients.


Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Cateteres Cardíacos/efeitos adversos , Reestenose Coronária/terapia , Estenose Coronária/terapia , Stents Farmacológicos/efeitos adversos , Diálise Renal/métodos , Idoso , Angioplastia Coronária com Balão/instrumentação , Angioplastia Coronária com Balão/métodos , Estudos de Casos e Controles , Causas de Morte , Materiais Revestidos Biocompatíveis , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/mortalidade , Estenose Coronária/diagnóstico por imagem , Feminino , Seguimentos , Hospitais Universitários , Humanos , Estimativa de Kaplan-Meier , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Revascularização Miocárdica/métodos , Revascularização Miocárdica/mortalidade , Paclitaxel/farmacologia , Pontuação de Propensão , Diálise Renal/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
5.
Zhongguo Zhong Yao Za Zhi ; 44(10): 2072-2077, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31355563

RESUMO

Paclitaxel( PTX) is used as a broad spectrum anti-tumor medicine. However,serious drawbacks restrict clinical application of PTX. In this study,we prepared tumor-targeting and pH-sensitive lipoprotein-mimic nanocarrier containing paclitaxel( BSALC/DOPE-PTX) to study the effective antitumor activity. The in vivo targeting ability of the nanocarrier in tumor bearing nude mice was evaluated by using a Kodak in vivo imaging system FX PRO. The in vivo anti-tumor activity was evaluated in MDA-MB-231 tumor bearing mice,and representative sections were stained with hematoxylin and eosin( H&E),and examined by light microscopy. The results showed that DiR-loaded FA-BSA-LC/DOPE selectively targeted tumor,and had a relatively long residence in the tumor tissue. According to the in vivo anti-tumor activity study,FA-BSA-LC/DOPE-PTX exhibited an outstanding tumor inhibition effect with a tumor growth inhibition rate of 79.3%,and tumor tissue sections stained by hematoxylin and eosin( HE) showed severe necrosis areas and many dead cells with condensed nuclei in the FA-BSA-LC/DOPE-PTX group. Therefore,FA-BSA-LC/DOPE-PTX is a biocompatible,tumor-targeting and pH-sensitive lipoprotein-mimic nanocarrier,with a very marked anti-tumor activity in tumor-bearing mice in vivo.


Assuntos
Portadores de Fármacos , Lipoproteínas , Nanopartículas , Neoplasias Experimentais/tratamento farmacológico , Paclitaxel/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus
6.
Anticancer Res ; 39(7): 3633-3639, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262889

RESUMO

BACKGROUND/AIM: The aim of this study was to analyze the effect of DL-methadone on enhancing the action of the chemotherapeutic drugs cisplatin, doxorubicin, 5-fluoruracil (5-FU) and paclitaxel on head and neck squamous carcinoma (HNSCC) cell lines. MATERIALS AND METHODS: The chemotherapeutic drugs were applied alone or in combination with DL-methadone and cytotoxicity was analyzed by XTT assays. Expression of the µ-opioid receptor and the drug transporter p-glycoprotein were analyzed by qRT-PCR. RESULTS: The effect of DL-methadone strongly depended on the respective chemotherapeutic agent. The basic expression of the µ-opioid receptor was not associated with the effect of DL-methadone, rather its induction by chemotherapeutic drugs. Expression or expression induction of p-glycoprotein was higher in weak-responder cell lines. CONCLUSION: Enhancement of the toxicity of chemotherapeutic drugs by DL-methadone depends on the drug and on the cell line used.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Metadona/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Fluoruracila/farmacologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Paclitaxel/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
7.
Neoplasma ; 66(5): 746-755, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31169019

RESUMO

MiR-21-5p has been identified as an oncogene to enhance human tumor progression. Here, we explored the mechanism by which miR-21-5p regulated the progression and paclitaxel (PTX) resistance in drug-resistant breast cancer (BC) cell lines. qRT-PCR assays were used to assess the expression levels of miR-21-5p and PDCD4 mRNA, and western blotting was used to detect PDCD4 protein level in PTX-resistant BC cell lines. Dual-luciferase reporter assay was used to observe the interaction between miR-21-5p and PDCD4 in PTX-resistant BC cell lines. Cell proliferation ability and IC50 values of PTX were measured by CCK-8 assay, cell cycle progression and apoptosis were determined with flow cytometry analysis, and cell migration and invasion capacities were analyzed using Transwell assay. Xenograft mice assay was used to validate the important role of miR-21-5p as a regulator on PTX-resistance BC cells growth in vivo. Then, we found that miR-21-5p was upregulated and PDCD4 was downregulated in BC tissues and PTX-resistant BC cell lines. MiR-21-5p silencing or PDCD4 overexpression ameliorated PTX resistance and inhibited the progression in PTX-resistant BC cell lines. Moreover, PDCD4 was demonstrated to be a direct target of miR-21-5p. MiR-21-5p exerted its regulatory effect by PDCD4 in PTX-resistant BC cell lines. Additionally, miR-21-5p silencing inhibited tumor growth in vivo. Therefore, our study demonstrated that miR-21-5p silencing ameliorated PTX resistance and inhibited the progression in PTX-resistant BC cell lines at least partly by targeting PDCD4, providing miR-21-5p as an effective therapeutic target for PTX-resistant BC treatment.


Assuntos
Proteínas Reguladoras de Apoptose , Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , MicroRNAs , Paclitaxel , Proteínas de Ligação a RNA , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , MicroRNAs/metabolismo , Paclitaxel/farmacologia , Proteínas de Ligação a RNA/metabolismo
8.
Int J Nanomedicine ; 14: 3629-3644, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190816

RESUMO

Background: A very common and simple method (known as the blending method) to formulate drug delivery systems with required properties is to physically mix amphiphilic block copolymers with different hydrophobicity. In addition to its simplicity, this blending strategy could help avoid the time and effort involved in the synthesis of block copolymers with the desired structure required for specific drug formulations. Purpose: We used the blending strategy to design a system that could overcome the problem of high hydrophobicity and be a good candidate for drug product development using PEG-PLA-PEG triblock copolymers. Methods: Two types of PEG-PLA-PEG triblock copolymers with similar (long) PLA molecular weights (MWs) and different PEG MWs were synthesized. The micellar formulations were prepared by blending the two block copolymers in various ratios. The size and stability of the blending systems were subsequently investigated to optimize the formulations for further studies. The loading properties of doxorubicin or paclitaxel into the optimized blending system were compared to that in mono systems (systems composed of only a single type of triblock copolymer). In vitro and in vivo anti-cancer effects of the preparations were evaluated to assess the use of the blending system as an optimal nanomedicine platform for insoluble anticancer agents. Results: The blending system (B20 system) with an optimized ratio of the triblock copolymers overcame the drawbacks of mono systems. Drug uptake from the drug-loaded B20 system and its anticancer effects against KB cells were superior compared to those of free drugs (doxorubicin hydrochloride and free paclitaxel). In particular, doxorubicin-loaded B20 resulted in extensive doxorubicin accumulation in tumor tissues and significantly higher in vivo anti-cancer effects compared to free doxorubicin. Conclusion: The blending system reported here could be a potential nanoplatform for drug delivery due to its simplicity and efficiency for pharmaceutical application.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Nanopartículas/química , Tamanho da Partícula , Polímeros/química , Animais , Antineoplásicos/farmacologia , Coloides/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Células KB , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Paclitaxel/farmacologia , Poliésteres/química , Polietilenoglicóis/química , Solubilidade , Distribuição Tecidual/efeitos dos fármacos
9.
Cell Mol Biol Lett ; 24: 40, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223315

RESUMO

Paclitaxel is a well-known anticancer agent with a unique mechanism of action. It is considered to be one of the most successful natural anticancer drugs available. This study summarizes the recent advances in our understanding of the sources, the anticancer mechanism, and the biosynthetic pathway of paclitaxel. With the advancement of biotechnology, improvements in endophytic fungal strains, and the use of recombination techniques and microbial fermentation engineering, the yield of extracted paclitaxel has increased significantly. Recently, paclitaxel has been found to play a large role in tumor immunity, and it has a great potential for use in many cancer treatments.


Assuntos
Biotecnologia/métodos , Imunoterapia , Neoplasias/terapia , Paclitaxel/uso terapêutico , Animais , Antineoplásicos Fitogênicos/biossíntese , Antineoplásicos Fitogênicos/uso terapêutico , Fermentação , Fungos/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Paclitaxel/biossíntese , Paclitaxel/farmacologia
10.
Carbohydr Polym ; 216: 129-139, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047049

RESUMO

A novel biotin and arginine modified hydroxypropyl-ß-cyclodextrin (biotin-Arg(pbf)-HP-ß-CD) was successfully synthesized. The hydroxyl groups of HP-ß-CD on the primary faces were coupled with carboxyl groups of biotin using arginine as the functional spacer. Using biotin-Arg(pbf)-HP-ß-CD as the carrier, paclitaxel (PTX)-loaded nanoparticles were developed by modified emulsion solvent evaporation method. The optimized PTX-loaded biotin-Arg(pbf)-HP-ß-CD nanoparticles had a mean diameter of 121.9 nm and zeta potential of -57.7 mV. Transmission electron microscopy (TEM) observation revealed that the nanoparticles were spherical in shape. XRD spectra confirmed the successful encapsulation of PTX. Moreover, in vitro and in vivo evaluations were performed to demonstrate the superior antitumor activity of the PTX-loaded nanoparticles. The cellular uptake study demonstrated the biotin receptor-mediated endocytosis of biotin-Arg(pbf)-HP-ß-CD nanoparticles and the increase of cellular uptake by introduction of biotin and arginine. It can be concluded that the biotin-Arg(pbf)-HP-ß-CD nanoparticles are efficient tumor-targeting drug delivery systems for PTX.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Antineoplásicos/uso terapêutico , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/uso terapêutico , 2-Hidroxipropil-beta-Ciclodextrina/síntese química , 2-Hidroxipropil-beta-Ciclodextrina/toxicidade , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Arginina/análogos & derivados , Arginina/síntese química , Arginina/toxicidade , Biotina/análogos & derivados , Biotina/síntese química , Biotina/toxicidade , Carcinoma/tratamento farmacológico , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Feminino , Humanos , Células MCF-7 , Camundongos , Nanopartículas/toxicidade , Paclitaxel/química , Paclitaxel/farmacologia , Tamanho da Partícula , Neoplasias do Colo do Útero/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Molecules ; 24(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052317

RESUMO

Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming paclitaxel resistance is a difficult challenge at present. In this study, we developed nano drugs to treat paclitaxel-resistant lung adenocarcinoma. We selected cabazitaxel and ß-elemene, which have fewer issues with drug resistance, and successfully prepared cabazitaxel liposome, ß-elemene liposome and cabazitaxel-ß-elemene complex liposome with good flexibility. The encapsulation efficiencies of cabazitaxel and ß-elemene in these liposomes were detected by precipitation microfiltration and microfiltration centrifugation methods, respectively. Their encapsulation efficiencies were all above 95%. The release rates were detected by a dialysis method. The release profiles of cabazitaxel and ß-elemene in these liposomes conformed to the Weibull equation. The release of cabazitaxel and ß-elemene in the complex liposome were almost synchronous. The pharmacodynamics study showed that cabazitaxel flexible liposome and ß-elemene flexible liposome were relatively good at overcoming paclitaxel resistance on paclitaxel-resistant lung adenocarcinoma. As the flexible complex liposome, the dosage of cabazitaxel could be reduced to 25% that of the cabazitaxel injection while retaining a similar therapeutic effect. It showed that ß-elemene can replace some of the cabazitaxel, allowing the dosage of cabazitaxel to be reduced, thereby reducing the drug toxicity.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Lipossomos , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacocinética , Taxoides/administração & dosagem , Taxoides/farmacocinética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Lipossomos/química , Camundongos , Estrutura Molecular , Paclitaxel/farmacologia , Tamanho da Partícula , Sesquiterpenos/química , Taxoides/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Nanomedicine (Lond) ; 14(10): 1291-1306, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31084395

RESUMO

Aim: To investigate the immune responses and antitumor efficacy of immunoactive polysaccharide functionalized gold nanocomposites (APS-AuNP). Materials & methods: Immunoregulation of APS-AuNP on dendritic cells/T cells in vitro was evaluated by flow cytometry and their inhibitions against primary/metastatic tumors were determined on 4T1-bearing mice model. Results & conclusion: APS-AuNP exhibited remarkable capability to induce dendritic cells maturation through phenotypic markers with functional changes, which further promoted T-cell proliferation and enhanced cytotoxicity against 4T1 tumor cells. The inhibitory rate of APS-AuNP against 4T1 primary tumor growth and pulmonary metastasis in mice was higher than paclitaxel-treated group. In addition, APS-AuNP exhibited strong capability to increase the population of CD4+/CD8+ T lymphocytes as well as effector memory cells rather than central memory cells.


Assuntos
Adjuvantes Imunológicos/química , Antineoplásicos/química , Células Dendríticas/imunologia , Ouro/química , Nanocompostos/química , Polissacarídeos/química , Linfócitos T/imunologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Ativação Linfocitária , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Transplante de Neoplasias , Óxido Nítrico/metabolismo , Paclitaxel/química , Paclitaxel/farmacologia , Polissacarídeos/imunologia
13.
Life Sci ; 228: 135-144, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31047896

RESUMO

AIMS: Drug resistance is becoming a major clinical challenge to the success of breast cancer treatment. Compelling evidence has shown the association between the deregulated long non-coding RNAs (lncRNAs) and drug resistance in various malignancies. However, the effects of long intergenic noncoding RNA 00511 (LINC00511), a newly identified oncogenic lncRNA, on the drug resistance of breast cancer cells remain unknown. MAIN METHODS: RT-qPCR was performed to detect the expressions of LINC00511, miR-29c, and cyclin dependent kinase 6 (CDK6) in breast cancer tissues and cells. Pearson correlation analysis was used to analyze the correlation between miR-29c, CDK6 and LINC00511 expression in breast cancer tissues. The interactions between LINC00511, CDK6 and miR-29c were explored by luciferase reporter assay, RT-qPCR and western blot. MTT assay and flow cytometry analysis were applied to evaluate paclitaxel cytotoxicity. KEY FINDINGS: LINC00511 and CDK6 were upregulated while miR-29c was downregulated in breast cancer tissues and cells. miR-29c was negatively correlated with LINC00511 and CDK6 expression while LINC00511 was positively correlated with CDK6 expression in breast cancer tissues. LINC0051 directly interacted with miR-29c to suppress its expression. LINC00511 knockdown enhanced paclitaxel cytotoxicity in breast cancer cells by upregulating miR-29c. CDK6 was identified as a target of miR-29c. CDK6 knockdown attenuated the effects of miR-29c inhibition on paclitaxel cytotoxicity in breast cancer cells. LINC00511 positively regulated CDK6 expression in breast cancer cells. SIGNIFICANCE: LINC00511 knockdown enhanced paclitaxel cytotoxicity in breast cancer cells via regulating miR-29c/CDK6 axis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/genética , Quinase 6 Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Paclitaxel/farmacologia , RNA Longo não Codificante/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Pessoa de Meia-Idade
14.
Mol Med Rep ; 19(5): 4433-4440, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942454

RESUMO

MicroRNAs (miRNAs) are post­transcriptional regulators that mediate the initiation and progression of human cancer. Growing evidence suggests that deregulation of miRNA expression levels underlies chemo­resistance. To investigate whether miRNA­302a (miR­302a) is involved in mediating chemo­resistance to paclitaxel in prostate cancer, a series of in vitro analyses were performed in paclitaxel­resistant prostate cancer PC­3PR cells and non­resistant prostate cancer PC­3 cells. It was demonstrated that the expression of miR­302a was upregulated in PC­3PR cells. Notably, ectopic expression of miR­302a also increased resistance to paclitaxel in wild­type PC­3 cells. By contrast, silencing of miR­302a in PC­3PR cells sensitized the cells to paclitaxel. Gene and protein expression analyses suggested that the miR­302a target gene breast cancer resistance protein (BCRP) may mediate chemo­resistance to paclitaxel in PC­3PR cells. In conclusion, the data suggested that elevated miR­302a levels, in part, mediate sensitivity to paclitaxel in prostate cancer through the aberrant regulation of its downstream targets, AOF2, BCRP and permeability glycoprotein 1. These data have implications for the development of novel therapeutics in prostate cancer that may improve sensitivity to chemotherapeutics.


Assuntos
Resistencia a Medicamentos Antineoplásicos , MicroRNAs/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/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/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Histona Desmetilases/química , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Paclitaxel/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Regulação para Cima
15.
Gulf J Oncolog ; 1(29): 14-21, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30956192

RESUMO

BACKGROUND: Concurrent chemo-radiotherapy in breast cancer (BC) may yield better local control with minimal toxicity in node positive patients. The feasibility of paclitaxel with radiotherapy was assessed for tolerability, cosmetic outcome as well as local control. METHODS: A prospective feasibility study on forty-three female breast cancer with stage II-III was conducted after definite surgery (modified radical mastectomy and breast conservative surgery). Adjuvant chemotherapy given was 4 cycles AC (Doxorubicin 60mg/m2+ cyclophosphamide 600mg/m2) followed by 4 cycles of Paclitaxel 60mg/m2 weekly for 12 weeks concurrent with 3D Conformal radiotherapy in a dose of 5Gy/20ttt/4wks to the whole breast and supraclavicular nodal region. Boost of 10Gy/5ttt was given to the tumor bed in conservative cases. Evaluation of lung function was done by carbon monoxide diffusion. Radiotherapy toxicity and breast cosmesis were assessed by the RTOG and Harvard criteria respectively. The cosmesis was assessed and scored at the beginning and end of RT and every 6 months thereafter. This was done by patient (subjective score) and physician (objective score) by comparing it with the contralateral untreated breast. RESULTS: After a median follow up of 36 months, the overall survival and disease-free survival were 95% and 92.5% respectively with no local relapse or radiation pneumonitis. There was no significant change in carbon monoxide diffusion after radiotherapy (p: 0.55). There was 15% delay in radiotherapy mainly due to acute GIII skin toxicity (10%), followed equally by mucositis and wound gap (2.5%). The volume of the irradiated breast was correlated with acute cosmetic effect (p = 0.057) but not on the late skin toxicity (p = 0.56). At the last follow up, the majority of patients declared excellent score in 62.5%, good in 20%, fair in 10% and poor in 7.5%. Subjective patient's satisfaction for the shape, color and size of the treated breast was 93%. CONCLUSION: Concurrent chemo-radiotherapy with weekly paclitaxel minimized the treatment duration with acceptable tolerance, cosmesis and good local control.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Paclitaxel/uso terapêutico , Adulto , Idoso , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/patologia , Estudos de Viabilidade , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/farmacologia , Estudos Prospectivos
16.
Mater Sci Eng C Mater Biol Appl ; 100: 247-259, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948059

RESUMO

The purpose of this study was to develop paclitaxel (PTX) formulations with solid dispersion (SD) and micelles (M) in order to improve solubility and oral absorption in rats. In addition, the enhanced anti-cancer effects of PTX formulations were compared in various breast cancer cell lines. The SD formulations with various copolymers were prepared using a solvent evaporation method, and micelles with Soluplus® mixed with d-α-tocopheryl polyethylene glycol-1000-succinate (TPGS) were prepared using a film hydration method. The physical properties of SD and M formulations were evaluated. The dissolution (%) of SD4 and SD9 formulations, and the solubility of M2 were significantly higher than those of PTX. The SD formulations and micelles were also stable for 3 and 1 month, respectively. The anti-cancer effects of SD4, SD9, and M2 significantly increased in breast cancer cells, whereas the blank formulations were not toxic to normal cells. The SD4, SD9 and M formulations improved the permeability of Cou-6 compared to Cou-6 solution in Madin-Darby canine kidney cells (MDCK line). The SD formulations and micelles had enhanced bioavailability (BA) compared to that of PTX, showing relative BA values of 667.3% (SD4), 359.6% (SD9), and 365.4% (M2). This study demonstrates the technologies to increase the anti-cancer effects and BA of PTX, via SD and micelle formulations, and, to our knowledge, is the first comparison of the two formulations.


Assuntos
Antineoplásicos/farmacologia , Micelas , Paclitaxel/farmacologia , Polímeros/química , Administração Oral , Animais , Disponibilidade Biológica , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cães , Liberação Controlada de Fármacos , Concentração Inibidora 50 , Células Madin Darby de Rim Canino , Masculino , Paclitaxel/sangue , Permeabilidade , Ratos Sprague-Dawley
17.
Mol Cancer ; 18(1): 89, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999914

RESUMO

BACKGROUND: The biology function of antisense intronic long noncoding RNA (Ai-lncRNA) is still unknown. Meanwhile, cancer patients with paclitaxel resistance have limited therapeutic options in the clinic. However, the potential involvement of Ai-lncRNA in paclitaxel sensitivity remains unclear in human cancer. METHODS: Whole transcriptome sequencing of 33 breast specimens was performed to identify Ai-lncRNA EGOT. Next, the role of EGOT in regulation of paclitaxel sensitivity was investigated. Moreover, the mechanism of EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions was investigated in detail. Furthermore, upstream transcriptional regulation of EGOT expression was also investigated by co-immunoprecipitation and chromatin immunoprecipitation. Finally, clinical breast specimens in our cohort, TCGA and ICGC were applied to validate the role of EGOT in enhancing of paclitaxel sensitivity. RESULTS: EGOT enhances autophagosome accumulation via the up-regulation of ITPR1 expression, thereby sensitizing cells to paclitaxel toxicity. Mechanistically, on one hand, EGOT upregulates ITPR1 levels via formation of a pre-ITPR1/EGOT dsRNA that induces pre-ITPR1 accumulation to increase ITPR1 protein expression in cis. On the other hand, EGOT recruits hnRNPH1 to enhance the alternative splicing of pre-ITPR1 in trans via two binding motifs in EGOT segment 2 (324-645 nucleotides) in exon 1. Moreover, EGOT is transcriptionally regulated by stress conditions. Finally, EGOT expression enhances paclitaxel sensitivity via assessment of cancer specimens. CONCLUSIONS: These findings broaden comprehensive understanding of the biology function of Ai-lncRNAs. Proper regulation of EGOT may be a novel synergistic strategy for enhancing paclitaxel sensitivity in cancer therapy.


Assuntos
Autofagia/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Receptores de Inositol 1,4,5-Trifosfato/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Animais , Antineoplásicos Fitogênicos/farmacologia , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo , Humanos , Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inibidores , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Paclitaxel/farmacologia , Ligação Proteica , RNA de Cadeia Dupla/genética , RNA de Cadeia Dupla/metabolismo , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Sobrevida , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Asia Pac J Clin Oncol ; 15(4): 250-256, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30938103

RESUMO

AIM: We investigated the efficacy, safety and optimal schedule of nanoparticle albumin-bound paclitaxel monotherapy as second- or third-line treatment for non-small-cell lung cancer patients without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement. METHODS: Patients with pretreated advanced non-small-cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement were included. The patients were administered 100 mg/m2 of nanoparticle albumin-bound paclitaxel on days 1, 8, 15 and 22 (level 0) or on days 1, 8 and 15 (level -1) every 4 weeks during phase I of the trial. The primary endpoint was objective response rate. The estimated objective response rate was 15% and the threshold was 5% with an α error of 0.05 and ß error of 0.2 in phase II. RESULTS: The recommended schedule was determined as level -1 in phase I. The characteristics of the 55 patients enrolled in phase II were as follows: median age = 66 years, male/female = 40/15, second/third line = 34/21 and adenocarcinoma/squamous cell carcinoma/large cell carcinoma/others = 34/17/2/2. Objective response rate was 7.3% (95% confidence interval, 2.0-17.6%). Median progression-free survival was 3.4 months. Treatment-related grade 3 or 4 toxicities were neutropenia (36.4%), febrile neutropenia (5.5%) and pulmonary infection (3.6%). Three patients had grade 2 pneumonitis and one treatment-related death occurred due to adult respiratory distress syndrome. CONCLUSION: This study failed to meet predefined primary endpoints for pretreated patients with advanced non-small-cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement.


Assuntos
Albuminas/uso terapêutico , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêutico , Idoso , Albuminas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mutação , Paclitaxel/farmacologia
19.
Eur J Med Chem ; 171: 310-331, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30953881

RESUMO

Microtubules are a protein which is made of α- and ß-heterodimer. It is one of the main components of the cell which play a vital role in cell division especially in G2/M-phase. It exists in equilibrium dynamic of polymerization and depolymerization of α- and ß-heterodimer. It is one of the best targets for developing anti-cancer drugs. Various natural occurring molecules are well known for their anti-tubulin effect such as vinca, paclitaxel, combretastatin, colchicine etc. These microtubule-targeted drugs are acted through two processes (i) inhibiting depolymerization of tubulin (tubulin stabilizing agents) and (ii) inhibiting polymerization of tubulin (tubulin destabilizing agents). Now days, various binding domains have been explore through which these molecules are binding to tubulin but the three major binding domain of tubulin are taxol, vinca and colchicine binding domain. The present article mainly focus on the classification of various naturally occurring compounds on the basis of their inhibition processes (depolymerization and polymerization) and the site of interaction (targets taxol, vinca and colchicine binding domain) which has been hitherto reported. By placing all the naturally occurring taxol, vinca and colchicine binding site analogues at one place makes a better understanding of the tubulin interactions with known natural tubulin binders that would helps in the discovery of new and potent natural, semi-synthetic and synthetic analogues for treating cancer.


Assuntos
Produtos Biológicos/farmacologia , Colchicina/farmacologia , Paclitaxel/farmacologia , Tubulina (Proteína)/metabolismo , Vinca/química , Sítios de Ligação/efeitos dos fármacos , Produtos Biológicos/síntese química , Produtos Biológicos/química , Colchicina/síntese química , Colchicina/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Paclitaxel/síntese química , Paclitaxel/química , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade
20.
Molecules ; 24(7)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30978971

RESUMO

Cell-penetrating peptide [WR]5 has been previously shown to be an efficient molecular transporter for various hydrophilic and hydrophobic molecules. The peptide was synthesized using Fmoc/tBu solid-phase chemistry, and one arginine was replaced with one lysine to enable the conjugation with the anticancer drugs. Paclitaxel (PTX) was functionalized with an esterification reaction at the C2' hydroxyl group of PTX with glutaric anhydride and conjugated with the cyclic peptide [W(WR)4K(ßAla)] in DMF to obtain the peptide-drug conjugate PTX1. Furthermore, camptothecin (CPT) was modified at the C(20)-hydroxyl group through the reaction with triphosgene. Then, it was conjugated with two functionalized cyclic peptides through a formyl linker affording two different conjugates, namely CPT1 and CPT2. All the conjugates showed better water solubility as compared to the parent drug. The cytotoxicity assay of the drugs and their conjugates with the peptides were evaluated in the human breast cancer MCF-7 cell line. PTX inhibited cell proliferation by 39% while the PTX-peptide conjugate inhibited the proliferation by ~18% after 72 h incubation. On the other hand, CPT, CPT1, and CPT2 reduced the cell proliferation by 68%, 39%, and 62%, respectively, in the MCF-7 cell lines at 5 µM concentration after 72 h incubation.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Peptídeos Penetradores de Células/farmacologia , Peptídeos Cíclicos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Neoplasias da Mama/patologia , Camptotecina/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/síntese química , Peptídeos Penetradores de Células/química , Esterificação , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Paclitaxel/química , Paclitaxel/farmacologia , Peptídeos Cíclicos/síntese química , Técnicas de Síntese em Fase Sólida
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