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1.
Anticancer Res ; 40(1): 335-339, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892584

RESUMEN

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.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Docetaxel/farmacología , Terapia Molecular Dirigida , Receptores Androgénicos/metabolismo , Taxoides/farmacología , Anciano , Antagonistas de Receptores Androgénicos/uso terapéutico , Docetaxel/uso terapéutico , Humanos , Masculino , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Taxoides/uso terapéutico , Resultado del Tratamiento
2.
Anticancer Res ; 40(1): 109-119, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892559

RESUMEN

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.


Asunto(s)
Antineoplásicos/farmacología , Docetaxel/farmacología , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Animales , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Pharm Res ; 37(3): 36, 2020 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-31965346

RESUMEN

PURPOSE: We describe the preparation of injectable polymeric paste (IPP) formulations for local and sustained release of drugs. Furthermore, we include the characterization and possible applications of such pastes. Particular attention is paid to characteristics relevant to the successful clinical formulation development, such as viscosity, injectability, degradation, drug release, sterilization, stability performance and pharmacokinetics. METHODS: Paste injectability was characterized using measured viscosity and the Hagen-Poiseuille equation to determine injection forces. Drug degradation, release and formulation stability experiments were performed in vitro and drug levels were quantified using HPLC-UV methods. Pharmacokinetic evaluation of sustained-release lidocaine IPPs used five groups of six rats receiving increasing doses subcutaneously. An anti-cancer formulation was evaluated in a subcutaneous tumor xenograft mouse model. RESULTS: The viscosity and injectability of IPPs could be controlled by changing the polymeric composition. IPPs demonstrated good long-term stability and tunable drug-release with low systemic exposure in vivo in rats. Preliminary data in a subcutaneous tumor model points to a sustained anticancer effect. CONCLUSIONS: These IPPs are tunable platforms for local and sustained delivery of drugs and have potential for further clinical development to treat a number of diseases.


Asunto(s)
Portadores de Fármacos/química , Composición de Medicamentos/métodos , Pomadas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Anilidas/química , Anilidas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Docetaxel/química , Docetaxel/farmacología , Liberación de Fármacos , Estabilidad de Medicamentos , Humanos , Inyecciones , Lidocaína/química , Lidocaína/farmacocinética , Masculino , Ratones , Ratones Desnudos , Neoplasias Experimentales , Nitrilos/química , Nitrilos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Ratas , Compuestos de Tosilo/química , Compuestos de Tosilo/farmacología , Viscosidad
4.
Br J Radiol ; 93(1106): 20190742, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31778316

RESUMEN

OBJECTIVE: One of the major issues in current radiotherapy (RT) is the normal tissue toxicity. A smart combination of agents within the tumor would allow lowering the RT dose required while minimizing the damage to healthy tissue surrounding the tumor. We chose gold nanoparticles (GNPs) and docetaxel (DTX) as our choice of two radiosensitizing agents. They have a different mechanism of action which could lead to a synergistic effect. Our first goal was to assess the variation in GNP uptake, distribution, and retention in the presence of DTX. Our second goal was to assess the therapeutic results of the triple combination, RT/GNPs/DTX. METHODS: We used HeLa and MDA-MB-231 cells for our study. Cells were incubated with GNPs (0.2 nM) in the absence and presence of DTX (50 nM) for 24 h to determine uptake, distribution, and retention of NPs. For RT experiments, treated cells were given a 2 Gy dose of 6 MV photons using a linear accelerator. RESULTS: Concurrent treatment of DTX and GNPs resulted in over 85% retention of GNPs in tumor cells. DTX treatment also forced GNPs to be closer to the most important target, the nucleus, resulting in a decrease in cell survival and increase in DNA damage with the triple combination of RT/ GNPs/DTX vs RT/DTX. Our experimental therapeutic results were supported by Monte Carlo simulations. CONCLUSION: The ability to not only trap GNPs at clinically feasible doses but also to retain them within the cells could lead to meaningful fractionated treatments in future combined cancer therapy. Furthermore, the suggested triple combination of RT/GNPs/DTX may allow lowering the RT dose to spare surrounding healthy tissue. ADVANCES IN KNOWLEDGE: This is the first study to show intracellular GNP transport disruption by DTX, and its advantage in radiosensitization.


Asunto(s)
Antineoplásicos/farmacología , Docetaxel/farmacología , Oro/farmacología , Nanopartículas del Metal , Fármacos Sensibilizantes a Radiaciones/farmacología , Antineoplásicos/farmacocinética , Transporte Biológico , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Docetaxel/farmacocinética , Sinergismo Farmacológico , Femenino , Oro/farmacocinética , Células HeLa , Humanos , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Neoplasias de la Mama Triple Negativas/radioterapia , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/radioterapia
5.
Ultrasonics ; 101: 106033, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31561207

RESUMEN

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.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antineoplásicos Fitogénicos/farmacología , Docetaxel/farmacología , Nanopartículas/química , Paclitaxel/farmacología , Polietilenglicoles/farmacología , Ondas Ultrasónicas , Animales , Antineoplásicos Fitogénicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Docetaxel/química , Perros , Sistemas de Liberación de Medicamentos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Paclitaxel/química , Polietilenglicoles/química , Polímeros/química , Polímeros/farmacología , Células Tumorales Cultivadas
6.
Anticancer Res ; 39(11): 5991-5998, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31704824

RESUMEN

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.


Asunto(s)
Adenocarcinoma del Pulmón/metabolismo , Aurora Quinasa A/metabolismo , Resistencia a Antineoplásicos/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Neoplasias Pulmonares/metabolismo , FN-kappa B/metabolismo , Tolerancia a Radiación , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/radioterapia , Animales , Antineoplásicos/farmacología , Apoptosis , Aurora Quinasa A/genética , Proliferación Celular , Docetaxel/farmacología , Resistencia a Múltiples Medicamentos/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , FN-kappa B/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
7.
J Environ Pathol Toxicol Oncol ; 38(3): 217-227, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31679309

RESUMEN

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.


Asunto(s)
Antineoplásicos/farmacología , Docetaxel/farmacología , Lactonas/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Sesquiterpenos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Humanos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Neoplasias Gástricas/tratamiento farmacológico
8.
J Exp Clin Cancer Res ; 38(1): 414, 2019 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-31601253

RESUMEN

BACKGROUND: Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. An understanding of the mechanisms of tamoxifen resistance can guide development of efficient therapies to prevent drug resistance. METHODS: We first tested whether peptidylarginine deiminase 2 (PAD2) may be involved in tamoxifen-resistance in breast cancer cells. The effect of depleting or inhibiting PAD2 in tamoxifen-resistant MCF-7 (MCF7/TamR) cells was evaluated both in vitro and in vivo. We then investigated the potential of Cl-amidine, a PAD inhibitor, to be used in combination with tamoxifen or docetaxel, and further explored the mechanism of the synergistic and effective drug regimen of PADs inhibitor and docetaxel on tamoxifen-resistant breast cancer cells. RESULTS: We report that PAD2 is dramatically upregulated in tamoxifen-resistant breast cancer. Depletion of PAD2 in MCF7/TamR cells facilitated the sensitivity of MCF7/TamR cells to tamoxifen. Moreover, miRNA-125b-5p negatively regulated PAD2 expression in MCF7/TamR cells, therefore overexpression of miR-125b-5p also increased the cell sensitivity to tamoxifen. Furthermore, inhibiting PAD2 with Cl-amidine not only partially restored the sensitivity of MCF7/TamR cells to tamoxifen, but also more efficiently enhanced the efficacy of docetaxel on MCF7/TamR cells with lower doses of Cl-amidine and docetaxel both in vivo and in vivo. We then showed that combination treatment with Cl-amidine and docetaxel enhanced p53 nuclear accumulation, which synergistically induced cell cycle arrest and apoptosis. Meanwhile, p53 activation in the combination treatment also accelerated autophagy processes by synergistically decreasing the activation of Akt/mTOR signaling, thus enhancing the inhibition of proliferation. CONCLUSION: Our results suggest that PAD2 functions as an important new biomarker for tamoxifen-resistant breast cancers and that inhibiting PAD2 combined with docetaxel may offer a new approach to treatment of tamoxifen-resistant breast cancers.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Docetaxel/farmacología , Tamoxifeno/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis , Autofagia , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Docetaxel/uso terapéutico , Resistencia a Antineoplásicos , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ornitina/análogos & derivados , Ornitina/farmacología , Ornitina/uso terapéutico , /metabolismo , Tamoxifeno/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Pharm Res ; 36(12): 165, 2019 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-31646391

RESUMEN

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.


Asunto(s)
Antineoplásicos/química , Docetaxel/química , Portadores de Fármacos/química , Flavonoides/química , Micelas , Células Madre Neoplásicas/efectos de los fármacos , Antígeno AC133/metabolismo , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Docetaxel/farmacología , Flavonoides/farmacología , Células HT29 , Humanos , Células Madre Neoplásicas/metabolismo , Polihidroxietil Metacrilato/análogos & derivados , Polihidroxietil Metacrilato/química
10.
Pharm Res ; 36(11): 154, 2019 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-31482205

RESUMEN

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.


Asunto(s)
Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Dendrímeros/química , Docetaxel/química , Paclitaxel/química , Receptor ErbB-2/metabolismo , Trastuzumab/química , Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Docetaxel/farmacología , Interacciones de Drogas , Liberación de Fármacos , Colorantes Fluorescentes/química , Humanos , Paclitaxel/farmacología , Propiedades de Superficie , Trastuzumab/farmacología , Resultado del Tratamiento
11.
Anticancer Res ; 39(9): 4811-4816, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31519583

RESUMEN

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.


Asunto(s)
Antineoplásicos/farmacología , Docetaxel/farmacología , Inhibidores Enzimáticos/farmacología , gamma-Glutamilciclotransferasa/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Interferente Pequeño/genética , gamma-Glutamilciclotransferasa/genética , gamma-Glutamilciclotransferasa/metabolismo
12.
Biomed Pharmacother ; 118: 109374, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31545228

RESUMEN

Docetaxel (Doc) is the gold standard of care for castration-resistant prostate cancer (CRPC) patients, although the therapeutic effects are modest. Fuzheng Yiliu decoction (FZYL) comprises multiple herbs, and has been used for >10 years to treat various cancers, including hepatocellular tumors, malignant gastrointestinal tumors, and prostate cancer. In the study reported, we evaluated the anticancer effects of FZYL and of a combination of Doc and FZYL in CRPC tumor-bearing mice, and explored the underlying mechanisms. PC-3 tumor-bearing mice were treated with FZYL, Doc, Doc + FZYL or vehicle solution. Tumor volume was monitored, and tumor weight, proliferation and apoptosis of tumor tissues were measured. Deep sequencing was used to profile the miRNA expression patterns in tumor tissues. Our results suggested that FZYL alone could depress tumor growth, and the combination of Doc and FZYL treatment exhibited enhanced anticancer effects. Doc + FZYL regulated the expression of 10 miRNAs: miR-34b-5p, miR-674-3p, miR-140-3p, miR-342-3p, miR-214-3p, miR-149-5p, miR-378c, miR-29b-3p, miR-218-5p, and miR-378a-3p, involving in the PI3K-Akt pathway in the treatment of CRPC.


Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Docetaxel/uso terapéutico , Medicamentos Herbarios Chinos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Docetaxel/farmacología , Medicamentos Herbarios Chinos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Redes Reguladoras de Genes/efectos de los fármacos , Masculino , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología
13.
Int J Nanomedicine ; 14: 4931-4947, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31371941

RESUMEN

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.


Asunto(s)
Antineoplásicos/farmacología , Dendrímeros/química , Rayos Infrarrojos , Nanopartículas/química , Fototerapia , Animales , Proliferación Celular/efectos de los fármacos , Terapia Combinada , Docetaxel/farmacología , Endocitosis/efectos de los fármacos , Fluorescencia , Células Hep G2 , Calor , Humanos , Indoles/farmacología , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Oligopéptidos/química , Fotoquimioterapia , Propionatos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Nanomedicina Teranóstica
14.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-31412584

RESUMEN

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.


Asunto(s)
Antineoplásicos/farmacología , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/efectos de la radiación , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/efectos de la radiación , Melatonina/farmacología , Radiación Ionizante , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/efectos de la radiación , Aromatasa/metabolismo , Neoplasias de la Mama , Proteína alfa Potenciadora de Unión a CCAAT/genética , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Docetaxel/farmacología , Activación Enzimática/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Glándulas Mamarias Humanas/citología , PPAR gamma/genética , PPAR gamma/metabolismo , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/metabolismo , Vinorelbina/farmacología
15.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-31412591

RESUMEN

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.


Asunto(s)
Antineoplásicos/farmacología , Docetaxel/farmacología , Resistencia a Antineoplásicos/genética , Neoplasias de la Próstata/genética , Taxoides/farmacología , Tubulina (Proteína)/genética , Línea Celular Tumoral , Cromonas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Morfolinas/farmacología , Fosfohidrolasa PTEN/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Unión Proteica , Tubulina (Proteína)/metabolismo
16.
Mol Cell Biochem ; 461(1-2): 103-118, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31363957

RESUMEN

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.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Quinasa 5 del Receptor Acoplado a Proteína-G/metabolismo , Paclitaxel/farmacología , Acetilación , Apoptosis/efectos de los fármacos , Biocatálisis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Docetaxel/farmacología , Femenino , Quinasa 3 del Receptor Acoplado a Proteína-G/metabolismo , Quinasas de Receptores Acoplados a Proteína-G/metabolismo , Células HeLa , Histona Desacetilasa 6/metabolismo , Histonas/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosforilación/efectos de los fármacos , Fosfoserina/metabolismo , Unión Proteica/efectos de los fármacos , Tubulina (Proteína)/metabolismo
17.
J Microencapsul ; 36(6): 552-565, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31403342

RESUMEN

Taxane-based chemotherapy-loaded drug delivery systems have great potential for cancer treatment. The docetaxel (DTX)-loaded PAMAM-based poly (γ-benzyl-l-glutamate)-b-d-α-tocopheryl polyethylene glycol 1000 succinate (PAM-PBLG-b-TPGS) nanoparticles and the docetaxel (DTX)-loaded PAMAM-based poly (γ-benzyl-l-glutamate) (PAM-PBLG) nanoparticles were designed using a modified nanoprecipitation method. The particle size, encapsulation efficiency (EE), and in vitro release characteristics of the nanoparticles were tested. The effects of the two nanoparticles on the cellular uptake and cell viability on human cervical cancer cell line Hela and the human breast cancer cell line MCF-7 were compared. Furthermore, their antitumor efficiency was evaluated through in vivo tumour growth experiment in comparison with free DTX. PAM-PBLG-b-TPGS nanoparticles displayed high EE, smaller diameter, and a nice releasing profile. Besides, based on the high EE and 'self-controlled' drug release of the DTX-loaded PAM-PBLG-b-TPGS nanoparticles, they exhibited stronger cytotoxicity (lower survival rate) and higher uptake rate than DTX-loaded PAM-PBLG nanoparticles in Hela cells and MCF-7 cells. Furthermore, compared with DTX-loaded PAM-PBLG nanoparticles and free DTX, DTX-loaded PAM-PBLG-b-TPGS nanoparticles produced a potent anti-tumour effect. Thus, the DTX-loaded PAM-PBLG-b-TPGS nanoparticles provide a novel attractive nanocarrier for the DTX delivery of chemotherapy to human breast cancer cells and human cervical cancer cells.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Docetaxel/administración & dosificación , Portadores de Fármacos/química , Neoplasias del Cuello Uterino/tratamiento farmacológico , Vitamina E/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/patología , Dendrímeros/química , Docetaxel/farmacología , Docetaxel/uso terapéutico , Liberación de Fármacos , Femenino , Células HeLa , Humanos , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias del Cuello Uterino/patología
18.
J Photochem Photobiol B ; 199: 111598, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31465971

RESUMEN

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.


Asunto(s)
Antineoplásicos/farmacología , Docetaxel/farmacología , Portadores de Fármacos/química , Queratinas/química , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Porfirinas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Materiales Biocompatibles/química , Permeabilidad de la Membrana Celular , Supervivencia Celular/efectos de los fármacos , Composición de Medicamentos/métodos , Liberación de Fármacos , Sinergismo Farmacológico , Células HeLa , Humanos , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/química , Esferoides Celulares/efectos de los fármacos
19.
Drug Deliv ; 26(1): 708-716, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31290708

RESUMEN

In this study, a synthetic high-density lipoprotein (sHDL), peptide-based nanocarrier loaded with docetaxel (DTX) was constructed, against breast cancer. The thermodynamic and molecular dynamic analyses were conducted to examine the stability of nanoparticles synthesized from mimetic peptide 5 A and various types of phospholipids. Furthermore, the cellular uptake and in vivo fluorescence imaging analysis experiments, with scavenger receptor B-I (SR-BI) were carried out to examine the tumor-targeting ability of sHDL. The nanoparticles were investigated for their pharmacodynamic and cytotoxic effects to show their effectivity as anti-tumor agents. The results showed that the synthesized sHDL nanoparticles exhibited a high payload of DTX, sustained drug release properties, and excellent biocompatibility. Moreover, DTX-sHDL nanoparticles enhanced the uptake of DTX, increased the cytotoxicity against MCF-7 cells, and reduced the off-target side-effects to normal cells. Finally, experiments in 4T1 cell line-bearing mice indicate that inhibition of tumor growth by DTX-sHDL nanoparticles was superior to that of free DTX group. Thus, the sHDL nanoparticles are a promising drug delivery vehicle for improving the efficacy of anti-cancer drugs.


Asunto(s)
Antineoplásicos/administración & dosificación , Apolipoproteína A-I/química , Docetaxel/administración & dosificación , Portadores de Fármacos/química , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Nanopartículas/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Materiales Biomiméticos , Preparaciones de Acción Retardada , Docetaxel/farmacología , Docetaxel/uso terapéutico , Docetaxel/toxicidad , Células Epiteliales , Femenino , Humanos , Células MCF-7 , Ratones , Nanopartículas/toxicidad , Imagen Óptica , Péptidos/química , Receptores Depuradores de Clase B/metabolismo
20.
Drug Deliv ; 26(1): 744-755, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31340676

RESUMEN

A drug and gene co-delivery system with chemotherapeutic sensibilization was prepared and used for nasopharyngeal carcinoma therapy. For this purpose, the graphene oxide (GO) was conjugated with the redox hyperbranched poly(amido amine) (HPAA) and then the targeting molecule, transferrin (Tf), was also conjugated. The obtained Tf-HPAA-GO could co-deliver docetaxel (DOC) and MMP-9 shRNA plasmid (pMMP-9) effectively and showed the targeting effect to HNE-1 cells. The co-delivery system showed the effective drug and gene delivery ability with high cytotoxicity and gene transfection efficiency. Besides that, Tf-HPAA-GO/DOC also showed the chemotherapeutic sensibilization effect, the formulation containing HPAA segments showed much higher cytotoxicity than free DOC. Benefiting from the sensibilization effect and DOC/pMMP-9 co-delivery strategy, this Tf-HPAA-GO/DOC/pMMP-9 co-delivery system exhibited the significantly improved therapeutic efficacy to HNE-1 tumor in a combined manner which was confirmed by in vitro and in vivo assays. This strategy provided an easily delivery system combining the drug/gene co-delivery, chemotherapeutic sensibilization, and targeting into one single platform, which showed a promising application in cancer therapy.


Asunto(s)
Antineoplásicos/administración & dosificación , Docetaxel/administración & dosificación , Grafito/administración & dosificación , Metaloproteinasa 9 de la Matriz/genética , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Transferrina/administración & dosificación , Células 3T3 , Aminas/síntesis química , Aminas/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Terapia Combinada , Docetaxel/farmacología , Docetaxel/uso terapéutico , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Técnicas de Transferencia de Gen , Terapia Genética , Glutatión/metabolismo , Grafito/química , Inhibidores de la Metaloproteinasa de la Matriz/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/metabolismo
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