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1.
Mater Sci Eng C Mater Biol Appl ; 128: 112305, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474856

RESUMO

In spite of established evidence of the synergistic combination of hydrophobic anticancer molecule and microRNA for breast cancer treatment, their in vivo delivery has not been realized owing to their instability in the biological milieu and varied physicochemical properties. The present work reports folate targeted hybrid lipo-polymeric nanoplexes for co-delivering DTX and miR-34a. These nanoplexes exhibited a mean size of 129.3 nm with complexation efficiency at an 8:1 N/P ratio. The obtained nanoplexes demonstrated higher entrapment efficiency of DTX (94.8%) with a sustained release profile up to 85% till 48 h. Further, an improved transfection efficiency in MDA-MB-231 and 4T1 breast cancer cells was observed with uptake primarily through lipid-raft and clathrin-mediated endocytosis. Further, nanoplexes showed improved cytotoxicity (~3.5-5 folds), apoptosis (~1.6-2.0 folds), and change in expression of apoptotic genes (~4-7 folds) compared to the free treatment group in breast cancer cells. In vivo systemic administration of FA-functionalized DTX and FAM-siRNA-loaded nanoplexes showed an improved area under the curve (AUC) as well as circulation half-life compared to free DTX and naked FAM-labelled siRNA. Acute toxicity studies of the cationic polymer showed no toxicity at a dose equivalent to 10 mg/kg based on the hematological, biochemical, and histopathological examination.


Assuntos
Antineoplásicos , Neoplasias da Mama , MicroRNAs/administração & dosagem , Nanopartículas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Docetaxel/farmacologia , Portadores de Fármacos/uso terapêutico , Feminino , Ácido Fólico , Humanos , MicroRNAs/genética , Polímeros/uso terapêutico
2.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(8): 1220-1225, 2021 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-34549714

RESUMO

OBJECTIVE: To investigate the effect of DR5-mediated docetaxel-targeted lipid microbubbles (MBs) combined with ultrasound-targeted microbubble destruction on apoptosis and expressions of Bcl-2, nuclear factor-κB(NF-κB), caspase-8, and DR5 in human HepG2 cells. METHODS: HepG2 cells were treated with docetaxel at its 50% inhibitory concentration (IC50) of 5 nmol/L, docetaxel combined with ultrasound, blank MBs, blank MBs combined with ultrasound (0.5 W/cm2 for 45 s), drugloaded lipid MBs (DLLM), DLLM combined with ultrasound, DR5-mediated DLLM (DR5-DLLM), or DR5-DLLM combined with ultrasound.After the treatments, the cells were further cultured for 24 h, and CCK-8 assay, TUNEL staining and flow cytometry were used to assess cell proliferation, apoptosis, and cell cycle changes; the changes in mRNA and protein expression levels of Bcl-2, NF-κB, caspase-8, and DR5 were detected with RT-qPCR and Western blotting. RESULTS: Among all the treatments, DR5-DLLM combined with ultrasound produced the strongest effects to inhibit the proliferation (P < 0.001), promote apoptosis (P < 0.001), and cause G2/M cell cycle arrest (P < 0.001) in HepG2 cells.The combined treatment with DR5-DLLM and ultrasound also significantly downregulated Bcl-2 and NF-κB (P < 0.001) and upregulated DR5 and caspase-8 expressions (P < 0.001) at both the mRNA and protein levels. CONCLUSION: DR5-DLLM combined with ultrasound-targeted microbubble destruction can induce G2/M cell cycle arrest, proliferation inhibition and apoptosis in HepG2 cells by downregulating Bcl-2 and NF-κB and upregulating DR5 and caspase-8 expressions, indicating its value as a novel ultrasoundtargeted therapy for liver cancer.


Assuntos
Apoptose , Microbolhas , Proliferação de Células , Docetaxel/farmacologia , Células Hep G2 , Humanos , Lipídeos
3.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445110

RESUMO

Epidermal growth factor receptor (EGFR) is overexpressed in lung cancer patients. Despite treatment with various EGFR tyrosine kinase inhibitors, recurrence and metastasis of lung cancer are inevitable. Docetaxel (DTX) is an effective conventional drug that is used to treat various cancers. Several researchers have studied the use of traditional herbal medicine in combination with docetaxel, to improve lung cancer treatment. SH003, a novel herbal mixture, exerts anticancer effects in different cancer cell types. Here, we aimed to investigate the apoptotic and anticancer effects of SH003 in combination with DTX, in human non-small-cell lung cancer (NSCLC). SH003, with DTX, induced apoptotic cell death, with increased expression of cleaved caspases and cleaved poly (ADP-ribose) polymerase in NSCLC cells. Moreover, SH003 and DTX induced the apoptosis of H460 cells via the suppression of the EGFR and signal transducer and activator of transcription 3 (STAT3) signaling pathways. In H460 tumor xenograft models, the administration of SH003 or docetaxel alone diminished tumor growth, and their combination effectively killed cancer cells, with increased expression of apoptotic markers and decreased expression of p-EGFR and p-STAT3. Collectively, the combination of SH003 and DTX may be a novel anticancer strategy to overcome the challenges that are associated with conventional lung cancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células A549 , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
4.
Theranostics ; 11(16): 7813-7828, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335966

RESUMO

Non-invasive monitoring of hemodynamic tumor responses to chemotherapy could provide unique insights into the development of therapeutic resistance and inform therapeutic decision-making in the clinic. Methods: Here, we examined the longitudinal and dynamic effects of the common chemotherapeutic drug Taxotere on breast tumor (KPL-4) blood volume and oxygen saturation using eigenspectra multispectral optoacoustic tomography (eMSOT) imaging over a period of 41 days. Tumor vascular function was assessed by dynamic oxygen-enhanced eMSOT (OE-eMSOT). The obtained in vivo optoacoustic data were thoroughly validated by ex vivo cryoimaging and immunohistochemical staining against markers of vascularity and hypoxia. Results: We provide the first preclinical evidence that prolonged treatment with Taxotere causes a significant drop in mean whole tumor oxygenation. Furthermore, application of OE-eMSOT showed a diminished vascular response in Taxotere-treated tumors and revealed the presence of static blood pools, indicating increased vascular permeability. Conclusion: Our work has important translational implications and supports the feasibility of eMSOT imaging for non-invasive assessment of tumor microenvironmental responses to chemotherapy.


Assuntos
Neoplasias da Mama/metabolismo , Hemodinâmica/fisiologia , Tomografia Óptica/métodos , Animais , Neoplasias da Mama/diagnóstico por imagem , Linhagem Celular Tumoral , Docetaxel/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Hipóxia/metabolismo , Camundongos , Camundongos SCID , Oxigênio/metabolismo , Técnicas Fotoacústicas/métodos , Tomografia/métodos , Tomografia Computadorizada por Raios X/métodos , Microambiente Tumoral/fisiologia
5.
Anticancer Res ; 41(8): 3753-3758, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281834

RESUMO

BACKGROUND/AIM: Cabazitaxel is known to be effective in patients with castration-resistant prostate cancer (CRPC) showing resistance to docetaxel. The objective of this study was to investigate the molecular mechanism mediating cytotoxic activity of cabazitaxel in docetaxel-resistant human CRPC cells. MATERIALS AND METHODS: Parental human CRPC cell line PC3 (PC3/P) was continuously exposed to increasing doses of docetaxel, and a cell line resistant to docetaxel, PC3/R, was developed. Phenotypic differences between these cell lines were investigated. RESULTS: There were no significant differences in sensitivity to cabazitaxel between PC3/P and PC3/R. In PC3/P, both docetaxel and cabazitaxel markedly inhibited the phosphorylation of AKT serine/threonine kinase 1 (AKT) and p44/42 mitogen-activated protein kinase (MAPK). In PC3/R, however, phosphorylation of AKT and p44/42 MAPK were maintained following treatment with docetaxel, whereas treatment with cabazitaxel resulted in the marked down-regulation of phosphorylation of AKT but not that of p44/42 MAPK. Furthermore, additional treatment of PC3/R with a specific inhibitor of AKT significantly enhanced the cytotoxic activity of docetaxel but not that of cabazitaxel. Growth of PC3/R in nude mice after treatment with cabazitaxel was significantly inhibited compared with that after treatment with docetaxel. CONCLUSION: Antitumor activity of cabazitaxel in docetaxel-resistant CRPC cells was explained, at least in part, by the inactivation of persistently phosphorylated AKT even after treatment with docetaxel.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Taxoides/farmacologia , Animais , Cromonas/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Antígeno Ki-67/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Morfolinas/farmacologia , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Theranostics ; 11(14): 6873-6890, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093859

RESUMO

Rationale: Chemoresistance is a major obstacle in prostate cancer (PCa) treatment. We sought to understand the underlying mechanism of PCa chemoresistance and discover new treatments to overcome docetaxel resistance. Methods: We developed a novel phenotypic screening platform for the discovery of specific inhibitors of chemoresistant PCa cells. The mechanism of action of the lead compound was investigated using computational, molecular and cellular approaches. The in vivo toxicity and efficacy of the lead compound were evaluated in clinically-relevant animal models. Results: We identified LG1980 as a lead compound that demonstrates high selectivity and potency against chemoresistant PCa cells. Mechanistically, LG1980 binds embryonic ectoderm development (EED), disrupts the interaction between EED and enhancer of zeste homolog 2 (EZH2), thereby inducing the protein degradation of EZH2 and inhibiting the phosphorylation and activity of EZH2. Consequently, LG1980 targets a survival signaling cascade consisting of signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B 1 (ABCB1) and survivin. As a lead compound, LG1980 is well tolerated in mice and effectively suppresses the in vivo growth of chemoresistant PCa and synergistically enhances the efficacy of docetaxel in xenograft models. Conclusions: These results indicate that pharmacological inhibition of EED-EZH2 interaction is a novel strategy for the treatment of chemoresistant PCa. LG1980 and its analogues have the potential to be integrated into standard of care to improve clinical outcomes in PCa patients.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Descoberta de Drogas/métodos , Resistencia a Medicamentos Antineoplásicos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Complexo Repressor Polycomb 2/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Sinergismo Farmacológico , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Complexo Repressor Polycomb 2/química , Complexo Repressor Polycomb 2/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Quinases Associadas a Fase S/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Survivina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Oral Pathol Med ; 50(8): 795-802, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34157171

RESUMO

BACKGROUND: Annexin A1, a member of the Annexin superfamily, has been shown to play a vital role in a broad range of molecular and cellular processes. This study aims to explore the relationship between the Annexin A1 expression and the clinical response to cisplatin, docetaxel and 5-fluorouracil (TPF) as induction chemotherapy in patients with oral squamous cell carcinoma (OSCC). METHODS: This study recruited two hundred thirty-two patients from a III/IVA OSCC trial. Immunohistochemistry was used to assess the level of Annexin A1 expression. Overexpression and knockdown methods in HB96, HN4 and CAL27 cell lines were used to assess the role of Annexin A1 in the neoplastic cellular response to chemotherapy. RESULTS: We found that reduced expression of Annexin A1 conferred a prognostic benefit from induction chemotherapy based on the TPF drug combination in patients with moderately/poorly differentiated disease. Using an in vitro model, we found that low Annexin A1 enhanced cellular proliferation by activating the EGFR/AKT signalling pathway and inhibiting p27 expression. Furthermore, low Annexin A1 initiated a significant decrease in cell viability after treatment with TPF agents. In addition, downregulation of Annexin A1 promoted apoptosis induced by docetaxel, cisplatin and 5-fluorouracil, and upregulation of Annexin A1 inhibited apoptosis. CONCLUSION: Annexin A1 may be of prognostic value in patients with locally advanced OSCC who are managed with TPF chemotherapy, as low Annexin A1 promotes chemosensitivity to TPF chemotherapy in oral cancer cells via enhanced caspase-dependent apoptosis.


Assuntos
Anexina A1 , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Anexina A1/genética , Anexina A1/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Fluoruracila/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Quimioterapia de Indução , Neoplasias Bucais/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Taxoides/uso terapêutico
8.
Genes (Basel) ; 12(5)2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069563

RESUMO

Castration-resistant prostate cancer (CRPC) is an advanced stage of prostate cancer that can progress rapidly even in patients treated with castration. Previously, we found that tumor-associated macrophages (TAM) can be recruited by CSF-1 secreted by docetaxel-treated prostate cancer cells and promote the survival of cancer cells in response to chemotherapy. The inhibition of CSF-1R can impede this effect and significantly prolong survival in xenograft mice. However, the actual mechanism of how TAM improves cancer cell survival still remains elusive and controversial. Here, for the first time, we found that the enhanced survival of cancer cells achieved by TAM was mainly mediated by CXCR4 activation from the increased secretion of CXCL12 from CSF-1 activated TAM. This finding helps to clarify the mechanism of chemoresistance for second-line chemotherapy using docetaxel, facilitating the development of novel drugs to overcome immune tolerance in castration-resistant prostate cancer.


Assuntos
Sobrevivência Celular/genética , Quimiocina CXCL12/genética , Fator Estimulador de Colônias de Macrófagos/genética , Neoplasias de Próstata Resistentes à Castração/genética , Receptores CXCR4/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Macrófagos Associados a Tumor/patologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Docetaxel/farmacologia , Humanos , Masculino , Camundongos , Células PC-3 , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Macrófagos Associados a Tumor/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Molecules ; 26(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068627

RESUMO

α-Trifluoromethyl chalcones were prepared and evaluated for their antiproliferative activities against androgen-independent prostate cancer cell lines as well as five additional types of human tumor cell lines. The most potent chalcone 5 showed superior antitumor activity in vivo with both oral and intraperitoneal administration at 3 mg/kg. Cell-based mechanism of action studies demonstrated that 5 induced cell accumulation at sub-G1 and G2/M phases without interfering with microtubule polymerization. Furthermore, several cancer cell growth-related proteins were identified by using chalcone 5 as a bait for the affinity purification of binding proteins.


Assuntos
Antineoplásicos/farmacologia , Chalconas/farmacologia , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Docetaxel/farmacologia , Humanos , Masculino , Camundongos SCID , Taxoides/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
BMC Cancer ; 21(1): 629, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34044797

RESUMO

BACKGROUND: Despite considerable medical proceedings, cancer is still a leading cause of death. Major problems for tumor therapy are chemoresistance as well as toxic side effects. In recent years, the additional treatment with the antidiabetic drug metformin during chemotherapy showed promising results in some cases. The aim of this study was to develop an in vitro tumor therapy model in order to further investigate the potential of a combined chemotherapy with metformin. METHODS: Cytotoxic effects of a combined treatment on BALB/c fibroblasts were proven by the resazurin assay. Based on the BALB/c cell transformation assay, the BALB/c tumor therapy model was established successfully with four different and widely used chemotherapeutics from different categories. Namely, Doxorubicin as a type-II isomerase inhibitor, Docetaxel as a spindle toxin, Mitomycin C as an alkylating agent and 5-Fluorouracil as an antimetabolite. Moreover, glucose consumption in the medium supernatant was measured and protein expressions were determined by Western Blotting. RESULTS: Initial tests for the combined treatment with metformin indicated unexpected results as metformin could partly mitigate the cytotoxic effects of the chemotherapeutic agents. These results were further confirmed as metformin induced resistance to some of the drugs when applied simultaneously in the tumor therapy model. Mechanistically, an increased glucose consumption was observed in non-transformed cells as well as in the mixed population of malignant transformed cell foci and non-transformed monolayer cells, suggesting that metformin could also increase glucose consumption in transformed cells. CONCLUSION: In conclusion, this study suggests a cautious use of metformin during chemotherapy. Moreover, the BALB/c tumor therapy model offers a potent tool for further mechanistic studies of drug-drug interactions during cancer therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Metformina/farmacologia , Neoplasias/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Células 3T3 BALB , Carcinógenos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Meios de Cultura/metabolismo , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Glucose/metabolismo , Humanos , Metformina/uso terapêutico , Metilcolantreno/toxicidade , Camundongos , Mitomicina/farmacologia , Mitomicina/uso terapêutico
11.
Mater Sci Eng C Mater Biol Appl ; 124: 112033, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33947535

RESUMO

Glioblastoma multiforme (GBM) is a first primary Central Nervous System tumor with high incidence and lethality. Its treatment is hampered by the difficulty to overcome the blood-brain barrier (BBB) and by the non-specificity of chemotherapeutics to tumor cells. This study was based on the development characterization and in vitro efficacy of folate-modified TPGS transfersomes containing docetaxel (TF-DTX-FA) to improve GBM treatment. TF-DTX-FA and unmodified transfersomes (TF-DTX) were prepared through thin-film hydration followed by extrusion technique and characterized by physicochemical and in vitro studies. All formulations showed low particles sizes (below 200 nm), polydispersity index below 0.2, negative zeta potential (between -16.75 to -12.45 mV) and high encapsulation efficiency (78.72 ± 1.29% and 75.62 ± 0.05% for TF-DTX and TF-DTX-FA, respectively). Furthermore, cytotoxicity assay of TF-DTX-FA showed the high capacity of the nanocarriers to reduce the viability of U-87 MG in both 2D and 3D culture models, when compared with DTX commercial formulation and TF-DTX. In vitro cellular uptake assay indicated the selectivity of transfersomes to tumoral cells when compared to normal cells, and the higher ability of TF-DTX-FA to be internalized into 2D U-87 MG in comparison with TF-DTX (72.10 and 62.90%, respectively, after 24 h). Moreover, TF-DTX-FA showed higher permeability into 3D U-87 MG spheroid than TF-DTX, suggesting the potential FA modulation to target treatment of GBM.


Assuntos
Antineoplásicos , Glioblastoma , Nanopartículas , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Docetaxel/farmacologia , Portadores de Fármacos , Ácido Fólico , Glioblastoma/tratamento farmacológico , Humanos , Vitamina E
12.
Mater Sci Eng C Mater Biol Appl ; 124: 112039, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33947539

RESUMO

In this study, to improve the intestinal absorption of small molecule chemotherapeutic drug docetaxel (DTX) and macromolecular monoclonal antibody drug bevacizumab (BVZ), we designed and prepared a type of co-delivery nanoparticles for the oral administration of DTX and BVZ. Carboxymethyl chitosan (CMC) and poly(lactic-co-glycolic acid) (PLGA) were used as the carrier of DTX nanoparticles (CPNPDTX), and methoxy polyethylene glycol-poly (ß-amino ester) (mPEG-PAE) was used as the carrier of BVZ nanoparticles (PPNPBVZ). Then, the two nanoparticles were physically mixed in mass ratios to form mixed co-delivery nanoparticles, which was named as CPNPDTX&PPNPBVZ. The nanoparticles were characterized with pH-sensitive drug release property. CPNPDTX&PPNPBVZ could significantly increase the bioavailability of DTX and BVZ according to the more cellular uptake in Caco-2 cells and the higher absorption in the intestinal tissue. Compared with free DTX and BVZ, CPNPDTX&PPNPBVZ showed excellent cytotoxic effects on A549 cells. Our study revealed the potential of co-delivery nanoparticles of binary mixture of chemotherapeutic small molecule and macromolecular antibody drug as an oral administration therapeutic system.


Assuntos
Antineoplásicos , Nanopartículas , Administração Oral , Antineoplásicos/farmacologia , Bevacizumab/farmacologia , Células CACO-2 , Docetaxel/farmacologia , Portadores de Fármacos , Humanos , Absorção Intestinal
13.
ACS Appl Mater Interfaces ; 13(22): 25635-25648, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34038097

RESUMO

Metastasis is the main cause of death in cancer patients. The efficacy of pharmacological therapy for cancer is limited by the heterogeneous nature of cancer cells and the lack of knowledge of microenvironments in metastasis. Evidence has shown that activated platelets possess both tumor-homing and metastasis-targeting properties via intrinsic cell adhesion molecules on platelets, and malaria protein VAR2CSA is able to specifically bind to oncofetal chondroitin sulfate, which is overexpressed on cancer cells with both epithelial and mesenchymal phenotypes. Inspired by these mechanisms, we developed a recombinant VAR2CSA peptide (rVAR2)-modified activated platelet-mimicking nanoparticles (rVAR2-PM/PLGA-ss-HA) by coating the surface of disulfide-containing biodegradable PLGA conjugate nanoparticles (PLGA-ss-HA) with an activated platelet membrane. The results demonstrated that the engineered 122 nm rVAR2-PM/PLGA-ss-HA inherited the innate properties of the activated platelet membrane and achieved enhanced homing to both primary and metastatic foci. The nanoparticles were endocytosed and responded to a high intracellular concentration of reduced glutathione, resulting in nanoparticle disintegration and the release of chemotherapeutic drugs to kill tumor cells. Thus, rVAR2-decorated activated platelet-targeting nanoparticles with controlled drug release provide a promising drug delivery strategy for efficient treatment of primary and metastatic cancer.


Assuntos
Antígenos de Protozoários/metabolismo , Plaquetas/química , Docetaxel/farmacologia , Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Nanopartículas/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Membrana Celular/química , Sulfatos de Condroitina/metabolismo , Preparações de Ação Retardada , Docetaxel/química , Ácido Hialurônico/química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Masculino , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Ratos , Ratos Sprague-Dawley
14.
J Urol ; 206(3): 630-637, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33904759

RESUMO

PURPOSE: We aimed to explore the association between genomic status and clinical outcome of platinum-based chemotherapy among patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: We conducted a retrospective study of 55 patients with mCRPC who received platinum-based chemotherapy after the progression to docetaxel chemotherapy and underwent genomic profiling of 14 homologous recombination (HR) pathway genes. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. RESULTS: Of 55 patients, 23 harbored genomic defects in HR pathway genes. Median prostate specific antigen (PSA)-PFS for the HR defect group was 6.7 months compared with 2.6 months for the no HR defect group (p=0.001). The patients harboring somatic HR defect displayed shorter PSA-PFS than those harboring germline HR defect (4.5 months vs not available; p=0.066). The PSA50 (patients who survived for 12 weeks and had a PSA decline over 50% from baseline) response rate displayed higher in patients harboring BRCA2 or ATM defect (6/8, 75.0%) than in those harboring CDK12 defect (2/9, 22.2%; p=0.06). Patients harboring BRCA2 or ATM defect displayed prolonged PSA-PFS, compared with those harboring CDK12 defect and those harboring other HR defect (p=0.038). In multivariate Cox regression analysis, HR defect and BRCA2 or ATM defect were independent significant factors associated with superior PAS-PFS to platinum-based chemotherapy. CONCLUSIONS: The patients with mCRPC harboring alterations in different HR genes displayed distinct response to platinum-based chemotherapy. Patients with mCRPC harboring genomic defects in crucial HR genes either in the germline or somatic, especially BRCA2 and ATM, might experience superior outcomes to platinum-based chemotherapy, compared with those harboring CDK12 defect.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA2/genética , Biópsia , Carboplatina/farmacologia , Cisplatino/farmacologia , Quinases Ciclina-Dependentes/genética , Análise Mutacional de DNA , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Recombinação Homóloga/genética , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/secundário , Estudos Retrospectivos
15.
Nat Nanotechnol ; 16(7): 820-829, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33795849

RESUMO

The poor transport of molecular and nanoscale agents through the blood-brain barrier together with tumour heterogeneity contribute to the dismal prognosis in patients with glioblastoma multiforme. Here, a biodegradable implant (µMESH) is engineered in the form of a micrometre-sized poly(lactic-co-glycolic acid) mesh laid over a water-soluble poly(vinyl alcohol) layer. Upon poly(vinyl alcohol) dissolution, the flexible poly(lactic-co-glycolic acid) mesh conforms to the resected tumour cavity as docetaxel-loaded nanomedicines and diclofenac molecules are continuously and directly released into the adjacent tumour bed. In orthotopic brain cancer models, generated with a conventional, reference cell line and patient-derived cells, a single µMESH application, carrying 0.75 mg kg-1 of docetaxel and diclofenac, abrogates disease recurrence up to eight months after tumour resection, with no appreciable adverse effects. Without tumour resection, the µMESH increases the median overall survival (∼30 d) as compared with the one-time intracranial deposition of docetaxel-loaded nanomedicines (15 d) or 10 cycles of systemically administered temozolomide (12 d). The µMESH modular structure, for the independent coloading of different molecules and nanomedicines, together with its mechanical flexibility, can be exploited to treat a variety of cancers, realizing patient-specific dosing and interventions.


Assuntos
Implantes Absorvíveis , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular , Diclofenaco/farmacocinética , Diclofenaco/farmacologia , Docetaxel/farmacocinética , Docetaxel/farmacologia , Implantes de Medicamento/farmacocinética , Implantes de Medicamento/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Int J Nanomedicine ; 16: 2735-2749, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859475

RESUMO

Purpose: Nanocarriers, with a high drug loading content and good safety, to achieve desirable therapeutic effect are always the goals for industry and research. Methods and Results: In the present study, we developed a docetaxel loaded poly-2-oxazoline polymer micellar system which employed poly-2-butyl-2 oxazoline and poly-2-methyl-2 oxazoline as the hydrophobic chain and hydrophilic chain, respectively. This micellar system achieves a high load up to 25% against the docetaxel, and further demonstrates an IC50 as low as 40% of the commercialized docetaxel injection in vitro and a double maximum tolerated dose in MCF-7 cells in vivo. Conclusion: The high drug loading content, superior safety, and considerable anti-cancer activity make this newly developed docetaxel loaded poly(2-oxazoline) micelle go further in future clinical research.


Assuntos
Antineoplásicos/uso terapêutico , Docetaxel/uso terapêutico , Micelas , Neoplasias/tratamento farmacológico , Oxazóis/química , Células A549 , Animais , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Docetaxel/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Masculino , Dose Máxima Tolerável , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Tamanho da Partícula , Tensoativos/química , Distribuição Tecidual
17.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804124

RESUMO

The circadian clock driven by the daily light-dark and temperature cycles of the environment regulates fundamental physiological processes and perturbations of these sophisticated mechanisms may result in pathological conditions, including cancer. While experimental evidence is building up to unravel the link between circadian rhythms and tumorigenesis, it is becoming increasingly apparent that the response to antitumor agents is similarly dependent on the circadian clock, given the dependence of each drug on the circadian regulation of cell cycle, DNA repair and apoptosis. However, the molecular mechanisms that link the circadian machinery to the action of anticancer treatments is still poorly understood, thus limiting the application of circadian rhythms-driven pharmacological therapy, or chronotherapy, in the clinical practice. Herein, we demonstrate the circadian protein period 1 (PER1) and the tumor suppressor p53 negatively cross-regulate each other's expression and activity to modulate the sensitivity of cancer cells to anticancer treatments. Specifically, PER1 physically interacts with p53 to reduce its stability and impair its transcriptional activity, while p53 represses the transcription of PER1. Functionally, we could show that PER1 reduced the sensitivity of cancer cells to drug-induced apoptosis, both in vitro and in vivo in NOD scid gamma (NSG) mice xenotransplanted with a lung cancer cell line. Therefore, our results emphasize the importance of understanding the relationship between the circadian clock and tumor regulatory proteins as the basis for the future development of cancer chronotherapy.


Assuntos
Carcinogênese/genética , Neoplasias/genética , Proteínas Circadianas Period/genética , Proteína Supressora de Tumor p53/genética , Células A549 , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ritmo Circadiano/efeitos dos fármacos , Cisplatino/farmacologia , Docetaxel/farmacologia , Cronoterapia Farmacológica , Etoposídeo/farmacologia , Humanos , Camundongos , Neoplasias/patologia , Neoplasias/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int J Mol Sci ; 22(7)2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33916522

RESUMO

Our previous study found that zinc finger protein 71 (ZNF71) mRNA expression was associated with chemosensitivity and its protein expression was prognostic of non-small-cell lung cancer (NSCLC). The Krüppel associated box (KRAB) transcriptional repression domain is commonly present in human zinc finger proteins, which are linked to imprinting, silencing of repetitive elements, proliferation, apoptosis, and cancer. This study revealed that ZNF71 KRAB had a significantly higher expression than the ZNF71 KRAB-less isoform in NSCLC tumors (n = 197) and cell lines (n = 117). Patients with higher ZNF71 KRAB expression had a significantly worse survival outcome than patients with lower ZNF71 KRAB expression (log-rank p = 0.04; hazard ratio (HR): 1.686 [1.026, 2.771]), whereas ZNF71 overall and KRAB-less expression levels were not prognostic in the same patient cohort. ZNF71 KRAB expression was associated with epithelial-to-mesenchymal transition (EMT) in both patient tumors and cell lines. ZNF71 KRAB was overexpressed in NSCLC cell lines resistant to docetaxel and paclitaxel treatment compared to chemo-sensitive cell lines, consistent with its association with poor prognosis in patients. Therefore, ZNF71 KRAB isoform is a more effective prognostic factor than ZNF71 overall and KRAB-less expression for NSCLC. Functional analysis using CRISPR-Cas9 and RNA interference (RNAi) screening data indicated that a knockdown/knockout of ZNF71 did not significantly affect NSCLC cell proliferation in vitro.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like/biossíntese , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/biossíntese , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Docetaxel/farmacologia , Feminino , Humanos , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Neoplasias/genética , Paclitaxel/farmacologia , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Taxa de Sobrevida
19.
Colloids Surf B Biointerfaces ; 203: 111760, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33872827

RESUMO

The present study was designed to develop pH-sensitive lipid polymer hybrid nanoparticles (pHS-LPHNPs) for specific cytosolic-delivery of docetaxel (DTX). The pHS-LPHNPs-DTX formulation was prepared by self-assembled nano-precipitation technique and characterized for zeta potential, particle size, entrapment efficiency, polydispersity index (PDI), and in vitro drug release. In vitro cytotoxicity of pHS-LPHNPs-DTX was assessed on breast cancer cells (MDA-MB-231 and MCF-7) and compared with DTX-loaded conventional LPHNPs and bare DTX. In vitro cellular uptake in MDA-MB-231 cell lines showed better uptake of pHS-LPHNPs. Further, a significant reduction in the IC50 of pHS-LPHNPs-DTX against both breast cancer cells was observed. Flow cytometry results showed greater apoptosis in case of pHS-LPHNPs-DTX treated MDA-MB-231 cells. Breast cancer was experimentally induced in BALB/c female mice, and the in vivo efficacy of the developed pHS-LPHNPs formulation was assessed with respect to the pharmacokinetics, biodistribution in the vital organs (liver, kidney, heart, lungs, and spleen), percentage tumor burden, and survival of breast cancer-bearing animals. In vivo studies showed improved pharmacokinetic and target-specificity with minimum DTX circulation in the deep-seated organs in the case of pHS-LPHNPs-DTX compared to the LPHNPs-DTX and free DTX. Mice treated with pHS-LPHNPs-DTX exhibited a significantly lesser tumor burden than other treatment groups. Also, reduced distribution of DTX in the serum was evident for pHS-LPHNPs-DTX treated mice compared to the LPHNPs-DTX and free DTX. In essence, pHS-LPHNPs mediated delivery of DTX presents a viable platform for developing therapeutic-interventions against breast-cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama , Nanopartículas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Docetaxel/farmacologia , Portadores de Fármacos/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Distribuição Tecidual
20.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33921035

RESUMO

Acquired treatment resistance is an important cause of death in prostate cancer, and this study aimed to explore the mechanisms of chemotherapy resistance in prostate cancer. We employed castration-resistant prostate cancer (CRPC), neuroendocrine prostate cancer (NEPC), and chemotherapy-resistant prostate cancer datasets to screen for potential target genes. The Cancer Genome Atlas (TCGA) was used to detect the correlation between the target genes and prognosis and clinical characteristics. Nei endonuclease VIII-like 3 (NEIL3) knockdown cell lines were constructed with RNA interference. Prostate cancer cells were treated with enzalutamide for the androgen deprivation therapy (ADT) model, and with docetaxel and cisplatin for the chemotherapy model. Apoptosis and the cell cycle were examined using flow cytometry. RNA sequencing and western blotting were performed in the knockdown Duke University 145 (DU145) cell line to explore the possible mechanisms. The TCGA dataset demonstrated that high NEIL3 was associated with a high T stage and Gleason score, and indicated a possibility of lymph node metastasis, but a good prognosis. The cell therapy models showed that the loss of NEIL3 could promote the chemotherapy resistance (but not ADT resistance) of prostate cancer (PCa). Flow cytometry revealed that the loss of NEIL3 in PCa could inhibit cell apoptosis and cell cycle arrest under cisplatin treatment. RNA sequencing showed that the knockdown of NEIL3 changes the expression of neuroendocrine-related genes. Further western blotting revealed that the loss of NEIL3 could significantly promote the phosphorylation of ATR serine/threonine kinase (ATR) and ATM serine/threonine kinase (ATM) under chemotherapy, thus initiating downstream pathways related to DNA repair. In summary, the loss of NEIL3 promotes chemotherapy resistance in prostate cancer, and NEIL3 may serve as a diagnostic marker for chemotherapy-resistant patients.


Assuntos
Resistencia a Medicamentos Antineoplásicos , N-Glicosil Hidrolases/deficiência , Neoplasias da Próstata/tratamento farmacológico , Antagonistas de Androgênios/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , N-Glicosil Hidrolases/genética , N-Glicosil Hidrolases/metabolismo , Invasividade Neoplásica , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fase S/efeitos dos fármacos
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