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1.
Anticancer Res ; 40(1): 109-119, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892559

RESUMO

BACKGROUND/AIM: Although molecular targeting therapy is an attractive treatment for cancer, resistance eventually develops in most cases. Here, we evaluated chemotherapeutic efficacy on non-small cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor inhibitors mechanistically. MATERIALS AND METHODS: Antitumor effects of taxotere were evaluated using multiple models, including xenograft, and patient-derived models developed from adenocarcinoma cancer patients. Protein expressions were analyzed after drug treatment. RESULTS: Taxotere inhibited tumor growth of NSCLC cells harboring drug resistance, and reduced the expression of phosphorylated MET proto-oncogene, receptor tyrosine kinase (MET). A tumor-inhibitory effect of taxotere was also demonstrated in vivo in xenografts in mice, patient-derived primary lung tumor cells and patient-derived xenograft with concomitant repression of phosphorylated MET expression. Chemotherapeutic and MET-targeting drug exhibited a synergistic cell growth-inhibitory effect. CONCLUSION: These results suggest that the anticancer drug taxane may be an adjuvant for lung tumors exhibiting enhanced signaling of MET networks.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Anticancer Res ; 40(1): 335-339, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892584

RESUMO

BACKGROUND/AIM: The novel taxane cabazitaxel has been shown to exert excellent anticancer effects after androgen receptor axis-targeting (ARAT) agents in clinical data, but not in in vitro data. We investigated the clinical outcome of cabazitaxel chemotherapy after docetaxel according to use of ARAT agents. PATIENTS AND METHODS: Prostate specific antigen (PSA) response, progression-free survival, and overall survival were compared between cases with and without prior use of ARAT agents in 74 Japanese patients with metastatic castration-resistant prostate cancer treated with cabazitaxel chemotherapy. RESULTS: Background characteristics were comparable between patients with and without prior use of ARAT agents. PSA response, progression-free survival, and overall survival in cabazitaxel chemotherapy were comparable between patients with and without prior use of ARAT agents. CONCLUSION: No detrimental effects of prior ARAT agents on clinical outcome were observed for cabazitaxel chemotherapy in the post-docetaxel setting, suggesting that cabazitaxel can be expected to remain active even after ARAT agent therapy.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Docetaxel/farmacologia , Terapia de Alvo Molecular , Receptores Androgênicos/metabolismo , Taxoides/farmacologia , Idoso , Antagonistas de Receptores de Andrógenos/uso terapêutico , Docetaxel/uso terapêutico , Humanos , Masculino , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/uso terapêutico , Resultado do Tratamento
3.
Ultrasonics ; 101: 106033, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31561207

RESUMO

The objective of this study was to use ultrasound in combination with nanoparticulate formulations of taxane drugs for an additive approach to overcome multidrug resistance (MDR). Polymeric nanoparticulate formulations containing both chemotherapeutic taxane drugs and a polymeric inhibitor (MePEG17-b-PCL5) of drug resistant proteins have been previously developed in an attempt to overcome MDR in cells. High frequency (>1 MHz) ultrasound has been shown to increase the uptake of cytotoxic drugs in MDR proliferating cells and has been suggested as a different way to overcome MDR, resensitize drug resistant cancer cells and allow for chemotherapeutic efficacy. MDCK-MDR cells were incubated with docetaxel (DTX) or paclitaxel (PTX) loaded, solid core, nanoparticles made from a 50:50 ratio of two diblock copolymers, MePEG114-b-PCL200 and MePEG17-b-PCL5 (PCL200/PCL5). The accumulation of drug in MDCK-MDR cells was measured using radiolabeled drug and the viability of cells was determined using an MTS cell proliferation assay. The effect of ultrasound (4 MHz, 32 W/cm2, 10 s, 25% duty cycle) on drug uptake and cell viability was studied. Using free DTX or PTX, MDCK-MDR cells were killed at sublethal doses of drug with the P-gp inhibitor (MePEG17-b-PCL5) present at a concentration of just 0.006% (m/v) and cell death began after just 3 h of incubation. Using sublethal incubation doses of PTX or DTX in PCL200/PCL5 nanoparticles for 90 min, followed by a second exposure to blank PCL200/PCL5 nanoparticles, cell viability dropped by approximately 60% at 24 h. Drug accumulation increased by 1.43-1.9 fold following five bursts of ultrasound applied at 90 min. Both, increased ultrasound exposure and increased concentrations of blank nanoparticles during the second incubation allowed for increased levels of cell death. The combined use of ultrasound with taxane and P-gp inhibitor loaded polymeric nanoparticles may allow for increased accumulation of drug and inhibitor which may then release both agents inside cells in a controlled manner to overcome drug resistance in MDR cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Docetaxel/farmacologia , Nanopartículas/química , Paclitaxel/farmacologia , Polietilenoglicóis/farmacologia , Ondas Ultrassônicas , Animais , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/química , Cães , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Paclitaxel/química , Polietilenoglicóis/química , Polímeros/química , Polímeros/farmacologia , Células Tumorais Cultivadas
4.
J Environ Pathol Toxicol Oncol ; 38(3): 217-227, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679309

RESUMO

BACKGROUND: Natural active components have been reported to serve as adjuvant medications in the clinical practice of cancer therapeutics. However, the antineoplastic roles of atractylenolide III (ATL) are rarely reported. In the present study, we assessed the functions of ATL combined with docetaxel in gastric cancer cells. METHODS: Cell viability and cytotoxic activity were evaluated using CCK-8 and LDH-based cytotoxicity assays, respectively. Protein expression levels were measured by western blotting analysis. Annexin V-FITC/PI staining was used to evaluate cell apoptosis using flow cytometry. RESULTS: AGS and SGC-7901 cell viability was significantly inhibited in ATL combined with docetaxel group compared with docetaxel treatment alone. The levels of LDH, apoptosis rate, and the ratio of BAX to Bcl-2 were significantly elevated in combination treatment group compared to docetaxel treatment alone. Intriguingly, docetaxel combined with ATL resulted in a significant decrease in FGFR1, FGFR2, and FGFR4 protein expression compared with docetaxel treatment alone. Knockout of FGFR1, -2, and -4 exhibited a similar role of medications to inhibit growth and induce apoptosis in AGS and SGC-7901 cells. CONCLUSIONS: ATL and docetaxel treatment performed the synergistic effects on the inhibition of growth and induction of apoptosis in gastric cancer cells, and the underlying mechanism was mediated, at least partially, through the inhibition of FGFR1, -2, and -4.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Lactonas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Sesquiterpenos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Neoplasias Gástricas/tratamento farmacológico
5.
Anticancer Res ; 39(11): 5991-5998, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704824

RESUMO

BACKGROUND/AIM: This study aimed to discuss the effect and possible molecular mechanisms of Aurora-A/NF-ĸB signaling on the radiotherapy resistance of human docetaxel-resistant lung adenocarcinoma cells. MATERIALS AND METHODS: The human lung adenocarcinoma SPC-A1 and SPC-A1/DTX cell lines were utilized in the present study. The MTT assay measured the sensitivity of cells to radiotherapy. The tumor-initiating ability of the cells was detected in vitro by cloning assays. Apoptosis was quantified by flow cytometry. Real-time quantitative PCR and western blotting were used to detect the mRNA and protein expression of the Aurora-A/NF-ĸB, respectively. Tumors transplanted subcutaneously into nude mice were used to test the effect of Aurora-A on the in vivo sensitivity of the tumors to radiotherapy. RESULTS: The SPC-A1/DTX docetaxel-resistant lung adenocarcinoma cells were radio-resistant compared with the parental SPC-A1 cells. Up-regulated aurora-A was responsible for the in vitro radio-resistance of docetaxel-resistant SPC-A1/DTX cells. Nuclear transcription factor NF-ĸB was identified as a downstream target gene of Aurora-A in SPC-A1/DTX cells, and NF-ĸB also participated in the radio-resistance of SPC-A1/DTX cells regulated by Aurora-A. CONCLUSION: The Aurora-A/NF-ĸB pathway is association with radio-resistance of human lung adenocarcinoma docetaxel-resistant cells.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Aurora Quinase A/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias Pulmonares/metabolismo , NF-kappa B/metabolismo , Tolerância a Radiação , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/radioterapia , Animais , Antineoplásicos/farmacologia , Apoptose , Aurora Quinase A/genética , Proliferação de Células , Docetaxel/farmacologia , Resistência a Múltiplos Medicamentos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Pharm Res ; 36(12): 165, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646391

RESUMO

PURPOSE: Cancer stem cells (CSCs) have been suggested to represent the main cause of tumour progression, metastasis and drug resistance. Therefore, these cells can be an appropriate target to improve cancer treatment. METHODS: A novel biodegradable brush copolymeric micelle was synthesized by the ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. The obtained micelle was used for co-delivery of the anticancer drug docetaxel (DTX) and Chrysin (CHS) as an adjuvant on the CSCs originated from Human colon adenocarcinoma cell line. Cancer stem cells were enriched by MACS technique and characterized by flow cytometry analysis against CD133 marker. RESULTS: Data demonstrated that the micelles harbouring DTX@CHS had potential to reduce cancer stem cell viability compared to free DTX@CHS, single-drug formulations and the control group (p < 0.05). The combination effect of DTX and CHS formulated in micelle was synergistic in CSCs (CI < 1). The reactive oxygen species content was shown to increase after cell treatment with DTX@CHS loaded on micelles (p < 0.05). DTX@CHS-micelles inhibited cancer stem cell migration rate in vitro (p < 0.05), indicating an impaired metastasis activity. CONCLUSION: In conclusion, the synthesized DOX@CHS-micelles can be applied in the introduction of anticancer agents to resistant cancer population by further investigations.


Assuntos
Antineoplásicos/química , Docetaxel/química , Portadores de Fármacos/química , Flavonoides/química , Micelas , Células-Tronco Neoplásicas/efeitos dos fármacos , Antígeno AC133/metabolismo , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Docetaxel/farmacologia , Flavonoides/farmacologia , Células HT29 , Humanos , Células-Tronco Neoplásicas/metabolismo , Poli-Hidroxietil Metacrilato/análogos & derivados , Poli-Hidroxietil Metacrilato/química
7.
Anticancer Res ; 39(9): 4811-4816, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519583

RESUMO

BACKGROUND/AIM: γ-Glutamylcyclotransferase (GGCT) is highly expressed in many forms of cancer, and is a promising therapeutic target. The present study investigated whether inhibition of GGCT enhanced the antiproliferative effects of the drug docetaxel in prostate cancer cells. MATERIALS AND METHODS: Immunohistochemistry and western blot analysis were conducted to measure GGCT expression in prostate cancer tissue samples and cell lines. GGCT was inhibited using RNAi and a novel enzymatic inhibitor, pro-GA, and cell proliferation was evaluated with single and combination treatments of GGCT inhibitors and docetaxel. RESULTS: GGCT was highly expressed in cultured prostate cancer cells and patient samples. GGCT inhibition alone inhibited prostate cancer cell line proliferation and induced cellular senescence. GGCT inhibition in combination with apoptosis-inducing docetaxel had more potent antiproliferative effects than either drug used alone. CONCLUSION: GGCT inhibition may potentiate anticancer drug efficacy.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Inibidores Enzimáticos/farmacologia , gama-Glutamilciclotransferase/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/genética , gama-Glutamilciclotransferase/genética , gama-Glutamilciclotransferase/metabolismo
8.
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
9.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412584

RESUMO

Melatonin exerts oncostatic actions and sensitizes tumor cells to chemotherapeutics or radiation. In our study, we investigated the effects of docetaxel, vinorelbine, and radiation on human breast fibroblasts and its modulation by melatonin. Docetaxel or vinorelbine inhibits proliferation and stimulates the differentiation of breast preadipocytes, by increasing C/EBPα and PPARγ expression and by downregulating tumor necrosis factor α (TNFα), interleukin 6 (IL-6), and IL-11 expression. Radiation inhibits both proliferation and differentiation through the downregulation of C/EBPα and PPARγ and by stimulating TNFα expression. In addition, docetaxel and radiation decrease aromatase activity and expression by decreasing aromatase promoter II and cyclooxygenases 1 and 2 (COX-1 and COX-2) expression. Melatonin potentiates the stimulatory effect of docetaxel and vinorelbine on differentiation and their inhibitory effects on aromatase activity and expression, by increasing the stimulatory effect on C/EBPα and PPARγ expression and the downregulation of antiadipogenic cytokines and COX expression. Melatonin also counteracts the inhibitory effect of radiation on differentiation of preadipocytes, by increasing C/EBPα and PPARγ expression and by decreasing TNFα expression. Melatonin also potentiates the inhibitory effect exerted by radiation on aromatase activity and expression by increasing the downregulation of promoter II, and COX-1 and COX-2 expression. Our findings suggest that melatonin modulates regulatory effects induced by chemotherapeutic drugs or radiation on preadipocytes, which makes it a promising adjuvant for chemotherapy and radiotherapy sensibilization.


Assuntos
Antineoplásicos/farmacologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/efeitos da radiação , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos da radiação , Melatonina/farmacologia , Radiação Ionizante , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/efeitos da radiação , Aromatase/metabolismo , Neoplasias da Mama , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Docetaxel/farmacologia , Ativação Enzimática/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Glândulas Mamárias Humanas/citologia , PPAR gama/genética , PPAR gama/metabolismo , Prostaglandina-Endoperóxido Sintases/genética , Prostaglandina-Endoperóxido Sintases/metabolismo , Vinorelbina/farmacologia
10.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412591

RESUMO

Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias da Próstata/genética , Taxoides/farmacologia , Tubulina (Proteína)/genética , Linhagem Celular Tumoral , Cromonas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Masculino , Morfolinas/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Ligação Proteica , Tubulina (Proteína)/metabolismo
11.
Int J Nanomedicine ; 14: 4931-4947, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371941

RESUMO

Background: Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), is a promising noninvasive strategy in the treatment of cancers due to its highly localized specificity to tumors and minimal side effects to normal tissues. However, single phototherapy often causes tumor recurrence which hinders its clinical applications. Therefore, developing a NIR-guided dendritic nanoplatform for improving the phototherapy effect and reducing the recurrence of tumors by synergistic chemotherapy and phototherapy is essential. Methods: A fluorescent targeting ligand, insisting of ICG derivative cypate and a tumor penetration peptide iRGD (CRGDKGPDC), was covalently combined with PAMAM dendrimer to prepare a single agent-based dendritic theranostic nanoplatform iRGD-cypate-PAMAM-DTX (RCPD). Results: Compared with free cypate, the resulted RCPD could generate enhanced singlet oxygen species while maintaining its fluorescence intensity and heat generation ability when subjected to NIR irradiation. Furthermore, our in vitro and in vivo therapeutic studies demonstrated that compared with phototherapy or chemotherapy alone, the combinatorial chemo-photo treatment of RCPD with the local exposure of NIR light can significantly improve anti-tumor efficiency and reduce the risk of recurrence of tumors. Conclusion: The multifunctional theranostic platform (RCPD) could be used as a promising method for NIR fluorescence image-guided combinatorial treatment of tumor cancers.


Assuntos
Antineoplásicos/farmacologia , Dendrímeros/química , Raios Infravermelhos , Nanopartículas/química , Fototerapia , Animais , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Docetaxel/farmacologia , Endocitose/efeitos dos fármacos , Fluorescência , Células Hep G2 , Temperatura Alta , Humanos , Indóis/farmacologia , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oligopeptídeos/química , Fotoquimioterapia , Propionatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Nanomedicina Teranóstica
12.
J Photochem Photobiol B ; 199: 111598, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31465971

RESUMO

The combination of chemotherapy and photodynamic therapy (PDT) is considered a valuable strategy for increasing therapeutic response in cancer treatment, and the re-formulation of pharmaceuticals in biocompatible nanoparticles (NPs) is particularly appealing for the possibility of co-loading drugs exerting cytotoxicity by different mechanisms, with the aim to produce synergic effects. We report the in-water synthesis of a novel keratin-based nanoformulation for the co-delivery of the antimitotic Docetaxel (DTX) and the photosensitizer Chlorin e6 (Ce6). The drug-induced aggregation method allowed the formation of monodisperse NPs (DTX/Ce6-KNPs) with an average diameter of 133 nm and loaded with a drug ratio of 1:1.8 of Ce6 vs DTX. The efficacy of DTX/Ce6-KNPs was investigated in vitro in monolayers and spheroids of DTX-sensitive HeLa (HeLa-P) and DTX-resistant HeLa (HeLa-R) cells. In monolayers, the cytotoxic effects of DTX/Ce6-KNPs toward HeLa-P cells were comparable to those induced by free DTX + Ce6, while in HeLa-R cells the drug co-loading in KNPs produced synergic interaction between chemotherapy and PDT. Moreover, as respect to monotherapies, DTX/Ce6-KNPs induced stronger cytotoxicity to both HeLa-P and HeLa-R multicellular spheroids and reduced their volumes up to 50%. Overall, the results suggest that KNPs are very promising systems for the co-delivery of chemotherapeutics and PSs, favoring synergic interactions between PDT and chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Portadores de Fármacos/química , Queratinas/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Porfirinas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Materiais Biocompatíveis/química , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Células HeLa , Humanos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Esferoides Celulares/efeitos dos fármacos
13.
Mol Cell Biochem ; 461(1-2): 103-118, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31363957

RESUMO

G protein-coupled receptor kinases (GRKs) phosphorylate the activated forms of G protein-coupled receptors (GPCRs), leading to receptor desensitization and internalization. In addition, GRKs can modify the activity of many non-GPCR-signaling pathways as well, controlling other cellular functions beyond that directly associated with a GPCR. In this report, we show that cervical cancer HeLa cells and breast cancer MDA MB 231 cells with reduced GRK5 expression display increased sensitivity to the apoptotic effects of paclitaxel (Taxol). This effect in cancer cells with low GRK5 levels could be because of blunted histone deacetylase 6 (HDAC6) activity that leads to an increase in α-tubulin acetylation levels, which augments paclitaxel sensitivity. We demonstrate that GRK5 and HDAC6 form a signaling complex in cells and in vitro. GRK5 phosphorylates HDAC6 at Ser-21 to promote its deacetylase activity. Therefore, the GRK5-HDAC6 interaction may contribute to paclitaxel resistance in cancer cells.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Quinase 5 de Receptor Acoplado a Proteína G/metabolismo , Paclitaxel/farmacologia , Acetilação , Apoptose/efeitos dos fármacos , Biocatálise/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Docetaxel/farmacologia , Feminino , Quinase 3 de Receptor Acoplado a Proteína G/metabolismo , Quinases de Receptores Acoplados a Proteína G/metabolismo , Células HeLa , Desacetilase 6 de Histona/metabolismo , Histonas/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fosfosserina/metabolismo , Ligação Proteica/efeitos dos fármacos , Tubulina (Proteína)/metabolismo
14.
Zhongguo Zhong Yao Za Zhi ; 44(11): 2251-2259, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359650

RESUMO

Docetaxel-loaded nanomicelles were prepared in this study to improve the solubility and tumor targeting effect of docetaxel(DTX),and further evaluate their anticancer effects in vitro. PBAE-DTX nanomicelles were prepared by film-hydration method with amphiphilic block copolymer polyethyleneglycol methoxy-polylactide(PELA) and pH sensitive triblock copolymer polyethyleneglycol methoxy-polylactide-poly-ß-aminoester(PBAE) were used respectively to prepare PELA-DTX nanomicelles and PBAE-DTX nanomicelles. The nanomicelles were characterized by physicochemical properties and the activity of mice Lewis lung cancer cells was studied. The results of particle size measurement showed that the blank micelles and drug-loaded micelles had similar particle sizes, ranging from 10 to 100 nm. The particle size of PBAE micelles was changed under weak acidic conditions, with good pH response. The encapsulation efficiency of the above two types of DTX-loaded nanomicelles determined by HPLC was(93.8±1.70)% and(87.2±4.10)%, and the drug loading amount was(5.3±0.10)% and(4.9±0.05)%,respectively. Furthermore,the DTX micelles also showed significant inhibitory effects on Lewis lung cancer cells by MTT assay, and pH-sensitive PBAE-DTX showed better cytotoxicity. The results of flow cytometry indicated that,the apoptosis rate of lung cancer Lewis cells was(20.72±1.47)%,(29.71±2.38)%,and(40.91±1.90)%(P<0.05) at 48 h after treatment in DTX,PELA-DTX,and PBAE-DTX groups. The results showed that different docetaxel preparations could promote the apoptosis of Lewis cells, and PBAE-DTX had stronger apoptotic-promoting effect. The pH-sensitive DTX-loaded micelles are promising candidates in developing stimuli triggered drug delivery systems in acidic tumor micro-environments with improved inhibitory effects of tumor growth on Lewis lung cancer.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Neoplasias Pulmonares/patologia , Nanopartículas , Animais , Linhagem Celular Tumoral , Portadores de Fármacos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Micelas , Tamanho da Partícula , Taxoides
15.
IET Nanobiotechnol ; 13(4): 428-434, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31171748

RESUMO

Breast cancer is a major cause of cancer mortality. Regarding the advantages of polymeric nanoparticles as drug delivery systems with targeting potential, in this study the antitumor mechanism of targeted docetaxel polymeric nanoparticles of Ecoflex® was exploited. Since the overexpression of HER-2 receptor in breast cancer cases is associated with poor prognosis and more aggressive disease, the proposed nanoparticles were conjugated to HER-2 specific aptamer molecules. In vitro cytotoxicity was evaluated by MTT assay. Flow-cytometry analysis was performed to evaluate the cellular uptake of nanoparticles loaded with a fluorescent probe. Anti-migration effects of samples were studied. Annexin IV-FITC and propidium iodide were implemented to investigate apoptosis induction and cell cycle analysis. Enhanced cytotoxicity compared with free docetaxel was explained considering improved cellular uptake of the nanoparticles and induced apoptosis in a larger portion of cells. Lower relative migration demonstrated enhanced anti-migration effect of nanoparticles, and cell cycle was arrested in G2/M phase using both formulations so the anti-microtubule mechanism of the drug was not altered. Therefore, this system could offer a potential substitute for the currently marketed docetaxel formulations, which may reduce adverse effects of the drug, while further in vivo and clinical investigations are required.


Assuntos
Apoptose/efeitos dos fármacos , Docetaxel , Nanopartículas/química , Poliésteres/química , Receptor ErbB-2/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Docetaxel/química , Docetaxel/farmacologia , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Receptor ErbB-2/genética
16.
Molecules ; 24(11)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181726

RESUMO

A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and ßIII-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via carbonate containing-linked macrocyclization display increased cytotoxicity on drug-resistant tumors overexpressing both ßIII and P-gp, among which compound 22b, bearing a 2-m-methoxybenzoyl group together with a five-atom linker, was identified as the most potent. Molecular modeling suggested the improved cytotoxicity of 22b results from enhanced favorable interactions with the T7 loop region of ßIII.


Assuntos
Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Taxoides/síntese química , Taxoides/farmacologia , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Morte Celular/efeitos dos fármacos , Docetaxel/síntese química , Docetaxel/química , Docetaxel/farmacologia , Células HeLa , Humanos , Compostos Macrocíclicos/química , Simulação de Acoplamento Molecular , Paclitaxel/síntese química , Paclitaxel/química , Paclitaxel/farmacologia , Homologia Estrutural de Proteína , Taxoides/química , Tubulina (Proteína)/química
17.
Mater Sci Eng C Mater Biol Appl ; 102: 876-886, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147059

RESUMO

Inhibition of tumor angiogenesis is considered as a valuable clinical strategy to treat some tumors, although benefits in term of progression-free and overall survival have been modest. Recent findings have pushed toward the use of antiangiogenic drugs in combination with chemotherapy regimens to potentiate therapeutic outcome. Herein, we propose a novel type of biodegradable antiangiogenic core-shell polymeric nanoparticles (NPs) for the delivery of poorly water-soluble chemotherapeutics. An amphiphilic diblock copolymer of poly(ethyleneglycol)-poly(ε-caprolactone) (PEG-PCL) was conjugated with an anti-FLT1 hexapeptide (aFLT1) at -OH PEG end, mixed in appropriate ratios with a monomethoxy-PEG-PCL and nanoprecipitated to form core-shell aFLT1-bearing NPs (DBLaFLT1). DBLaFLT1 were <100 nm, exposed aFLT1 on the surface and showed a higher thickness of the external hydrophilic shell as compared to NPs that do not bear aFLT1 (DBL). Very interestingly, DBLaFLT1 showed an antiangiogenic activity in the human umbilical endothelial cells (HUVEC) tube formation assay three-fold higher than an equivalent dose of free aFLT1. To provide a proof-of-concept of DBLaFLT1 potential in the delivery of conventional chemotherapeutics, docetaxel (DTX) was selected as model drug. DBLaFLT1 entrapped DTX with high efficiency and sustained its release along time in simulated biological conditions. At a non-cytotoxic dose, DTX-loaded DBLaFLT1 almost completely abolished tube formation in HUVEC while inhibition of DTX loaded DBL was significantly lower. The cytotoxicity of DTX-loaded NPs in HUVEC and triple negative breast cancer cells (MDA-MB-231) was not significantly different from that of the free drug in a wide range of concentrations and up to 72 h. Studies carried out in MDA-MB-231 cells implanted in chicken embryo chorioallantoic membranes (CAMs) evidenced an antiangiogenic activity of DTX-loaded DBLaFLT1 higher as compared with that of both DTX-loaded DBL and free DTX. While cancer cell migration from the tumor site was unaffected, the anticancer activity of DTX-loaded NPs was higher than that of free DTX and maximized for DTX-DBLaFLT1. In perspective, these results suggest that the delivery approach proposed here can be applied to other lipophilic chemotherapeutics devoid of relevant antiangiogenic properties to improve the final therapeutic response.


Assuntos
Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Docetaxel/farmacologia , Nanopartículas/química , Peptídeos/química , Inibidores da Angiogênese/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Galinhas , Membrana Corioalantoide/efeitos dos fármacos , Membrana Corioalantoide/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , Poliésteres/síntese química , Poliésteres/química , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
18.
Nanoscale ; 11(23): 11285-11304, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31165845

RESUMO

The success of glioma chemotherapy is hampered by poor drug penetration ability across the blood-brain barrier (BBB) and low intratumoral drug concentration. Novel tumor-targeted delivery systems are useful in specifically accumulating in the tumor foci and penetrating into the glioma core after entering into the brain. Here we show that a multi-targeting hybrid nanocarrier (Pep-MLHA HNPs) system based on hyaluronic acid (HA)-modified polymer and a functional peptide possesses multi-target capability and stronger penetration ability into the core of three-dimensional tumor spheroids, could migrate efficiently across the BBB in vitro. The intensity of the Pep-MLHA HNPs after transporting across the BBB was 5.2-fold and 5.6-fold higher than that of ML NPs in C6 and U87 cells, respectively. More interestingly, this multi-targeting hybrid system displayed high colloidal stability in PBS solution, and weak negative zeta potential (-1.99 ± 0.655 mV) minimizing nonspecific interactions with plasma proteins and promoting long-term circulation in vivo. Additionally, the multi-targeting hybrid system induced enhanced tumor localization in U87 in situ-bearing nude mice and xenograft-bearing nude mice after systemic administration. Furthermore, docetaxel (DTX)-loaded Pep-MLHA HNPs showed negligible systemic toxicity and enhanced therapeutic efficacy, with significantly improved survival rates in intracranial C6 glioma-bearing rats. The 50% survival rate of DTX/Pep-MLHA HNPs-treated rats (40 days) was significantly longer than that of rats treated with NS (22 days), Taxotere® (25 days), DTX/ML NPs (25 days), DTX/Pep NPs (32 days) and DTX/MLHA NPs (29 days). All the results suggested that the multi-targeting hybrid nanocarrier system is promising for glioma treatment.


Assuntos
Barreira Hematoencefálica , Neoplasias Encefálicas , Docetaxel , Portadores de Fármacos , Glioblastoma , Nanopartículas , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Docetaxel/química , Docetaxel/farmacocinética , Docetaxel/farmacologia , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Glioblastoma/irrigação sanguínea , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Ácido Hialurônico/química , Ácido Hialurônico/farmacocinética , Ácido Hialurônico/farmacologia , Masculino , Camundongos , Camundongos Nus , Células NIH 3T3 , Nanopartículas/química , Nanopartículas/uso terapêutico , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Breast Cancer Res Treat ; 177(2): 357-367, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31236812

RESUMO

PURPOSE: The objective of this study was to investigate if DHA dietary supplementation enhances the anticancer actions of docetaxel (TXT) in two different drug resistant triple negative breast cancer (TNBC) patient-derived xenografts (PDX)s. METHODS: In two experiments, female NSG mice bearing TNBC PDXs were randomized to one of two nutritionally adequate diets (20% w/w): control (0% DHA), or DHA (3.9% w/w of total fat) and injected with 0 or 5 mg/kg TXT, twice weekly for 6 weeks (n = 8 per group). Treatment response was determined by significant differences in tumor weight, and apoptotic, proliferation and cell cycle markers at endpoint. RESULTS: Mice bearing MAXF574 xenografts fed DHA diet and treated with TXT had a 57% reduction in tumor weight compared to mice fed control diet (P < 0.004), a 64% reduction compared to control + TXT (P < 0.01) and a 34% reduction compared to DHA with no TXT (P < 0.04). DHA + TXT reduced MAXF401 xenografts growth compared to control and control + TXT (by 43% and 34%, respectively, P < 0.05). In both xenografts, DHA + TXT resulted in a higher expression of proapoptotic proteins Ripk1 and Bid, lower expression of proliferation marker Ki67 and anti-apoptotic proteins Bcl-2 and Parp, and a greater increase in cell cycle arrest as measured by decreased Survivin expression when compared to control + TXT mice (P < 0.05). CONCLUSIONS: This work is the first to confirm that DHA supplementation during chemotherapy treatment improves TXT action in two PDX models of TNBC. The results suggest that decreases in tumor size occurred via changes in apoptosis, cell proliferation, and cell cycle pathways.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Suplementos Nutricionais , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
EBioMedicine ; 44: 150-161, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31147293

RESUMO

BACKGROUND: Chemoresistance is a major obstacle for the effective treatment of lung adenocarcinoma (LAD). Forkhead box (FOX) proteins have been demonstrated to play critical roles in promoting epithelial-mesenchymal transition (EMT) and chemoresistance. However, whether FOX proteins contribute to the acquisition of EMT and chemoresistance in LAD remains largely unknown. METHODS: FOX-A1 expression was measured in LAD cells and tissues by qRT-PCR. The expression levels of EMT markers were detected by western blotting and immunofluorescence assay. The interaction between Sex determining region Y-box protein 5 (SOX5) and FOX-A1 was validated by chromatin immunoprecipitation sequence (ChIP-seq) and Chromatin immunoprecipitation (ChIP) assay. Kaplan-Meier analysis and multivariate Cox regression analysis were performed to analyze the significance of FOX-A1 and SOX5 expression in the prognosis of LAD patients. FINDINGS: FOX-A1 was upregulated in docetaxel-resistant LAD cells. High FOX-A1 expression was closely associated with a worse prognosis. Upregulation of FOX-A1 in LAD samples indicated short progression-free survival (PFS) and overall survival (OS). SOX5 is a new and direct target of FOX-A1 and was positively regulated by FOX-A1 in LAD cell lines. Knockdown of FOX-A1 or SOX5 reversed the chemoresistance of docetaxel-resistant LAD cells by suppressing cell proliferation, migration and EMT progress. INTERPRETATION: These data elucidated an original FOX-A1/SOX5 pathway that represents a promising therapeutic target for chemosensitizing LAD and provides predictive biomarkers for evaluating the efficacy of chemotherapies.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Fator 3-alfa Nuclear de Hepatócito/genética , Fatores de Transcrição SOXD/genética , Ativação Transcricional , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Animais , Apoptose/genética , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células , Modelos Animais de Doenças , Docetaxel/farmacologia , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Modelos Biológicos , Prognóstico , Ligação Proteica , Fatores de Transcrição SOXD/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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