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1.
Anticancer Res ; 39(10): 5483-5494, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570442

RESUMO

BACKGROUND/AIM: Canine mammary gland tumors (CMGTs) are the most common tumors in female dogs. Rivoceranib (also known as apatinib) is a novel anti-angiogenic tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor-2 (VEGFR2). The aim of this study was to disclose the antitumor effects of rivoceranib on CMGT cell lines. MATERIALS AND METHODS: The direct effects of rivoceranib on CMGT cells in vitro were analyzed by cell proliferation and migration assays. Cell-cycle distribution and apoptotic ratio were analyzed by flow cytometry. Expression levels of phosphorylated VEGFR2 were evaluated by western blot analysis. RESULTS: Rivoceranib treatment significantly reduced the proliferation and migration of CMGT cells in a dose-dependent manner. Flow cytometry results revealed significant increases in G0/G1 phase arrest and apoptosis proportional to the drug concentration used. Rivoceranib reduced the level of phosphorylated VEGFR2. CONCLUSION: We confirm that rivoceranib exerts antitumor effects on CMGT cells by inhibiting biological functions.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cães , Feminino , Fase G1/efeitos dos fármacos , Neoplasias Mamárias Animais/metabolismo , Fosforilação/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Anticancer Res ; 39(10): 5515-5524, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570445

RESUMO

BACKGROUND/AIM: Administration of cisplatin in cancer patients is limited by the kidney-related adverse effects; however, a protective strategy is absent. We hypothesized that fucoidan protects the proximal tubule epithelial (TH-1) cells against the effects of cisplatin. MATERIALS AND METHODS: To assess the effect of fucoidan, its effect on reactive oxygen species (ROS) formation, endoplasmic reticulum (ER) stress response, DNA damage response (DDR), apoptosis, and cell-cycle arrest in TH-1 cells was investigated. RESULTS: Cisplatin increased the accumulation of ROS, leading to excessive ER stress. In presence of cisplatin, treatment of TH-1 cells with fucoidan significantly reduced the ER stress by maintaining the complex of GRP78 with PERK and IRE1α. In particular, fucoidan enhanced the antioxidative capacity through up-regulation of PrPC Furthermore, fucoidan suppressed cisplatin-induced apoptosis and cell-cycle arrest, whereas silencing of PRNP blocked these effects of fucoidan. CONCLUSION: Fucoidan may be a potential adjuvant therapy for cancer patients treated with cisplatin as it preserves renal functionality.


Assuntos
Cisplatino/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Polissacarídeos/farmacologia , Substâncias Protetoras/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Regulação para Cima/efeitos dos fármacos , eIF-2 Quinase/metabolismo
3.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3391-3398, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602900

RESUMO

Tumors are major chronic diseases and seriously threaten human health all over the world. How to effectively control and cure tumors is one of the most pivotal problems in the medical field. At present,surgery,radiotherapy and chemotherapy are still the main treatment methods. However,the side effects of radiotherapy and chemotherapy cannot be underestimated. Therefore,it is of great practical significance to find new anti-cancer drugs with low toxicity,high efficiency and targeting to cancer cells. With the increasing incidence of tumor,the anti-tumor effect of traditional Chinese medicine has increasingly become a research hotspot. Triptolide,which is a natural diterpenoid active ingredient derived from of Tripterygium wilfordii,as one of the highly active components,has anti-inflammatory,immunosuppressive,anti-tumor and other multiple effects. A large number of studies have confirmed that it has good anti-tumor activity against various tumors in vivo and in vitro. It can play an anti-tumor role by inhibiting the proliferation of cancer cells,inducing apoptosis of cancer cells,inducing autophagy of cancer cells,blocking the cell cycle,inhibiting the migration,invasion and metastasis of cancer cells,reversing multidrug resistance,mediating tumor immunity and inhibiting angiogenesis. On the basis of literatures,this paper reviews the anti-tumor effect and mechanism of triptolide,and analyzes the current situation of triptolide combined with other chemotherapy drugs,in order to promote deep research and better clinical application about triptolide.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos/farmacologia , Neoplasias/tratamento farmacológico , Fenantrenos/farmacologia , Tripterygium/química , Apoptose , Autofagia , Pontos de Checagem do Ciclo Celular , Compostos de Epóxi/farmacologia , Humanos
4.
Anticancer Res ; 39(10): 5461-5471, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570440

RESUMO

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


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Piridinas/farmacologia , Células A549 , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo
5.
Tumour Biol ; 41(9): 1010428319873749, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31496424

RESUMO

Differentiation therapy is directed to the self-renewing cancer stem cells, as well as their progeny transit amplifying cells, to force them to mature to terminal differentiation. Differentiation therapy is effective in treatment of neuroblastomas and myeloid leukemias. Checkpoint inhibition therapy removes blocks to cancer reactive T-killer cells and allows them to react to malignant cells and limit the growth of cancer. The percentage of patients with a given cancer that responds to either therapy is less than hoped for, and the duration of response is variable. Multiplying the response rate (percentage of patients responding to therapy) by the duration of response may be used to derive a survival score for patients treated with differentiation therapy or checkpoint inhibition. By this criterion, differentiation therapy gives better survival scores than checkpoint inhibition. Yet, checkpoint inhibition is considered a great success, mostly because it may be applied to many different types of cancer, and differentiation therapy is considered relatively ineffective because it is limited to a few specific cancers. On the other hand, the cost of checkpoint inhibition treatment is 10-20 times more per patient than that of differentiation therapy. Hopefully, future combined treatments and advances in both approaches will increase the effectiveness of these cancer treatments.


Assuntos
Antineoplásicos/uso terapêutico , Sobreviventes de Câncer/estatística & dados numéricos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Neoplasias/mortalidade , Células-Tronco Neoplásicas/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Prognóstico , Taxa de Sobrevida
7.
Life Sci ; 234: 116783, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31442552

RESUMO

Breast cancer (BCa) is the most commonly diagnosed lethal cancer in women worldwide. Notch signaling pathway is directly linked to BCa recurrence and aggressiveness. Natural remedies are becoming a prime choice to overcome against cancer due to lesser side effect and cost-effectiveness. Bulbine frutescens (Asphodelaceae), a traditional medicinal plant in South Africa possess bioactive flavonoids and terpenoids. Polar (methanol) and non-polar (hexane) B. frutescens plant extracts were prepared. GC-MS analysis revealed the differential presence of secondary metabolites in both methanolic and hexane extracts. We hereby first time evaluated the anticancer potential of B. frutescens methanolic and hexane extract in triple-negative and luminal BCa cells. B. frutescens extracts significantly decreased cell viability (IC50 4.8-28.4 µg/ml) and induced cell cycle arrest at G1 phase in MDA-MB-231 and T47D cells as confirmed by spectrophotometry and flow cytometry technique. RT-PCR analysis of cell cycle (cyclin D1, CDK4, and p21) and apoptosis modulating genes (caspase 3, Bcl2 and survivin) revealed upexpression of p21, and caspase 3, and down expression of cyclin D1, CDK4, Bcl2 and survivin genes in extract-treated BCa cells. Fluorescence spectrophotometry and confocal microscopy showed B. frutescens induced nuclear morphology and mitochondrial integrity disruption, and increased reactive oxygen species production in MDA-MB-231 and T47D cells. Flow cytometric apoptosis analysis of B. frutescens extracts treated MDA-MB-231 cells showed ≈13% increase in early apoptotic population in comparison to non-treated cells. Dual-Luciferase Reporter assay confirmed notch promoter inhibitory activity of B. frutescens extracts. Moreover, RTPCR analysis showed down regulation of notch responsive genes (Hes1 and Hey1) at transcription levels in extract-treated BCa cells. Western Blot analysis showed increased procaspase 3 protein expression in extract-treated BCa cells. In all the assays methanolic extract showed better anti-cancer properties. Literature-based identification of methanol soluble phytochemicals in B. frutescens and in silico docking study revealed Bulbineloneside D as a potent ϒ-secretase enzyme inhibitor. In comparison to standard notch inhibitor, lead phytochemical showed two additional hydrophobic interactions with Ala80 and Leu81 amino acids. In conclusion, B. frutescens phytochemicals have cell cycle arrest, ROS production, apoptosis induction, and mitochondria membrane potential disruption efficacy in breast cancer cells. B. frutescens phytochemicals have the ability to downregulate the notch signaling pathway in triple-negative and luminal breast cancer cells.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Xanthorrhoeaceae/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
8.
Life Sci ; 233: 116713, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31386875

RESUMO

Lung cancer is the leading cause of cancer-related mortality worldwide. Treatment with immunotherapy has made a significant impact on the outcomes for those patients suffering from lung cancer and its usage is currently an established treatment modality. Immune checkpoint inhibition that has blocking antibodies which target cytotoxic T-lymphocyte antigen-4 (CTLA-4) along with the programmed cell death protein 1 (PD-1) pathway [programmed death - 1/programmed death-ligand 1 (PD-L1)] have shown promising results for numerous malignancies. Nivolumab and pembrolizumab have been approved as PD-1 blocking antibodies while atezolizumab, avelumab, and durvalumab are approved as PD-L1 blocking antibodies by 'US Food and Drug Administration'. Immune checkpoint inhibitors have been found to statistically improve the survival of patients with lung cancer and have emerged as the primary immunotherapy in lung cancer and have changed the treatment paradigm for advanced disease. Despite such benefits, treatment with immune checkpoint inhibitors is associated with a unique pattern of immune-related adverse effects or side effects. Also, resistance is routinely developing in patients treated with immune checkpoint inhibitors. The current review provides an overview of immune checkpoint inhibitor treatment in lung cancer, its resistance, and adverse effects.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Prognóstico
9.
Chem Pharm Bull (Tokyo) ; 67(10): 1076-1081, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31406093

RESUMO

Histone deacetylases (HDACs) are enzymes that play a key role in structural modification and gene expression. The overexpression of HDAC is associated with cancer, and thus inhibiting the enzyme could be an efficient cancer therapy. To discover new HDAC inhibitors (HDACis), we proposed an improved protocol combining a hierarchical pharmacophore search, molecular docking, and molecular dynamic simulations. The test results showed that the improved screening protocol effectively reduced the false-positive rates of drug-like chemicals. Based on the protocol, we obtained 16 hit compounds as potential HDACis from the Life Chemicals database. Enzyme inhibition experiments showed that two of the hit chemical compounds had HDAC-inhibitory effects. In vitro assays showed that Z165155756 could selectively inhibit the proliferation of cancer cells and specifically promoted apoptosis and induced G1/S phase arrest in A2780 cells. It may have potential therapeutic effects in ovarian cancer and is worthy of further investigation.


Assuntos
Antineoplásicos/análise , Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Histona Desacetilases/análise , Inibidores de Histona Desacetilases/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade
10.
JAMA ; 322(8): 764-774, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31454018

RESUMO

Importance: Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease. Observations: Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of ≥50%) and 40% among patients with ALK-positive tumors. Conclusions and Relevance: Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Pontos de Checagem do Ciclo Celular , Genes erbB-1 , Humanos , Imunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Intervalo Livre de Progressão , Taxa de Sobrevida
11.
Adv Exp Med Biol ; 1155: 543-553, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468430

RESUMO

Taurine transporter (TauT) has been identified as a target gene of p53 tumor suppressor. TauT is also found to be overexpressed in variety type of human cancers, such as leukemia. This study showed that expression of TauT was upregulated by c-Myc and c-Jun oncogenes. To explore whether blocking of TauT inhibits tumor development, the RNA interference (RNAi) and immune targeting approaches were tested in tumor cells in vitro and in p53 mutant mice in vivo. Knockdown of TauT expression by RNAi resulted in cell cycle G2 arrest and suppressed human breast cancer MCF-7 cells proliferation determined by colonies production and cell migration assays. Knockdown of TauT also rendered MCF-7 cells more susceptible to chemotherapeutic drug-induced apoptosis. An antibody specifically against TauT blocked taurine uptake and induced cell cycle G2 arrest leading to cell death of variety type of tumor cells without affecting the viability of normal mammalian cells. TauT peptide vaccination significantly increased median lifespan (1.5-fold) of the p53 null mice and rescued p53+/- mice by extending the median lifespan from 315 days to 621 days. Furthermore, single dose treatment of tumor-bearing (thymic lymphoma) p53 null mice with TauT peptide reduced tumor size by about 50% and significantly prolonged survival of these mice from average 7 days (after observing the thymic lymphoma) to 21 days. This finding demonstrates that a novel TauT peptide vaccine can delay, inhibit, and/or treat p53 mutation related spontaneous tumorigenesis in vivo. Therefore, TauT peptide may be used as a universal cancer vaccine to prevent and/or treat patients with p53 mutation-mediated cancers.


Assuntos
Vacinas Anticâncer , Imunoterapia , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Interferência de RNA , Proteína Supressora de Tumor p53/genética , Animais , Anticorpos Monoclonais/farmacologia , Pontos de Checagem do Ciclo Celular , Técnicas de Silenciamento de Genes , Genes jun , Genes myc , Humanos , Células MCF-7 , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Mutação , Taurina , Vacinas de Subunidades
12.
Int J Nanomedicine ; 14: 5503-5526, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410001

RESUMO

Background and purpose: Glioma is one of the most aggressive primary brain tumors and is incurable. Surgical resection, radiation, and chemotherapies have been the standard treatments for brain tumors, however, they damage healthy tissue. Therefore, there is a need for safe anticancer drug delivery systems. This is particularly true for natural prodrugs such as thymoquinone (TQ), which has a high therapeutic potential for cancers but has poor water solubility and insufficient targeting capacity. We have tailored novel core-shell nanoformulations for TQ delivery against glioma cells using mesoporous silica nanoparticles (MSNs) as a carrier. Methods: The core-shell nanoformulations were prepared with a core of MSNs loaded with TQ (MSNTQ), and the shell consisted of whey protein and gum Arabic (MSNTQ-WA), or chitosan and stearic acid (MSNTQ-CS). Nanoformulations were characterized, studied for release kinetics and evaluated for anticancer activity on brain cancer cells (SW1088 and A172) and cortical neuronal cells-2 (HCN2) as normal cells. Furthermore, they were evaluated for caspase-3, cytochrome c, cell cycle arrest, and apoptosis to understand the possible anticancer mechanism. Results: TQ release was pH-dependent and different for core and core-shell nanoformulations. A high TQ release from MSNTQ was detected at neutral pH 7.4, while a high TQ release from MSNTQ-WA and MSNTQ-CS was obtained at acidic pH 5.5 and 6.8, respectively; thus, TQ release in acidic tumor environment was enhanced. The release kinetics fitted with the Korsmeyer-Peppas kinetic model corresponding to diffusion-controlled release. Comparative in vitro tests with cancer and normal cells indicated a high anticancer efficiency for MSNTQ-WA compared to free TQ, and low cytotoxicity in the case of normal cells. The core-shell nanoformulations significantly improved caspase-3 activation, cytochrome c triggers, cell cycle arrest at G2/M, and apoptosis induction compared to TQ. Conclusion: Use of MSNs loaded with TQ permit improved cancer targeting and opens the door to translating TQ into clinical application. Particularly good results were obtained for MSNTQ-WA.


Assuntos
Antineoplásicos/uso terapêutico , Benzoquinonas/uso terapêutico , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Glioma/tratamento farmacológico , Nanopartículas/química , Dióxido de Silício/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Materiais Biocompatíveis/química , Encéfalo/patologia , Varredura Diferencial de Calorimetria , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quitosana/química , Citocromos c/metabolismo , Difusão , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Cinética , Nanopartículas/ultraestrutura , Porosidade , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria
13.
Int J Nanomedicine ; 14: 5527-5540, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413561

RESUMO

Background: Nonspecific tumor targeting, potential relapse and metastasis of tumor after treatment are the main barriers in clinical photodynamic therapy (PDT) for cancer, hence, inhibiting relapse and metastasis of tumor is significant issues in clinic. Purpose: In this work, chidamide as a histone deacetylases inhibitor (HADCi) was bound onto a pH-responsive block polymer folate polyethylene glycol-b-poly(aspartic acid) (PEG-b-PAsp) grafted folate (FA-PEG-b-PAsp) to obtain the block polymer folate polyethylene glycol-b-poly(asparaginyl-chidamide) (FA-PEG-b-PAsp-chidamide, FPPC) as multimodal tumor-targeting drug-delivery carrier to inhibiting tumor cell proliferation and tumor metastasis in mice. Methods: Model photosensitizer pyropheophorbide-a (Pha) was encapsulated by FPPC in PBS to form the polymer micelles Pha@FPPC [folate polyethylene glycol-b-poly(asparaginyl-chidamide) micelles encapsulating Pha]. Pha@FPPC was characterized by transmission electron microscope and dynamic light scattering; also, antitumor activity in vivo and in vitro were investigated by determination of cellular ROS level, detection of cell apoptosis and cell cycle arrest, PDT antitumor activity in vivo and histological analysis. Results: With favorable and stable sphere morphology under transmission electron microscope (TEM) (~93.0 nm), Pha@FPPC greatly enhanced the cellular uptake due to its folate-mediated effective endocytosis by mouse melanoma B16-F10 cells and the yield of ROS in tumor cells induced by PDT, and mainly caused necrocytosis and blocked cell growth cycle not only in G2 phase but also in G1/G0 phase after PDT. Pha@FPPC exhibited lower dark cytotoxicity in vitro and a better therapeutic index because of its higher dark cytotoxicity/photocytotoxicity ratio. Moreover, Pha@FPPC not only significantly inhibited the growth of implanted tumor and prolonged the survival time of melanoma-bearing mice due to both its folate-mediated tumor-targeting and selectively accumulation at tumor site by EPR (enhanced permeability and retention)effect as micelle nanoparticles but also remarkably prevented pulmonary metastasis of mice melanoma after PDT compared to free Pha, demonstrating its dual antitumor characteristics of PDT and HDACi. Conclusion: As a folate-mediated and acid-activated chidamide-grafted drug-delivery carrier, FPPC may have great potential to inhibit tumor metastasis in clinical photodynamic treatment for cancer because of its effective and multimodal tumor-targeting performance as photosensitizer vehicle.


Assuntos
Aminopiridinas/química , Benzamidas/química , Ácido Fólico/uso terapêutico , Micelas , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorofila/análogos & derivados , Clorofila/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Ácido Fólico/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/ultraestrutura , Fármacos Fotossensibilizantes/farmacologia , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo
14.
Int J Nanomedicine ; 14: 5581-5594, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413564

RESUMO

Background: Chronic myeloid leukemia (CML) is a myeloproliferative disorder due to the existence of BCR-ABL fusion protein that allows the cells to keep proliferating uncontrollably. Although tyrosine kinase inhibitors can inhibit the activity of BCR-ABL fusion protein to trigger the cells apoptosis, drug resistance or intolerance exists in part of CML patients. Arsenic sulfide in its raw form (r-As4S4) can be orally administrated and certain therapeutic effects have been found out in the treatment of hematologic malignancies through inducing cell apoptosis. Methods: In this work, a water-dissolvable arsenic sulfide nanoformualtion (ee-As4S4) composed of As4S4 particulates with 470 nm in diameter and encapsulated by a kind of hydrophilic polymer was fabricated and applied to the CML cell line K562, K562/AO2 and primary cells from the bone marrow of CML patients. Results: Results showed that instead of inhibiting the activity of BCR-ABL, ee-As4S4 induced direct degradation of BCR-ABL in K562 cells within 6 hr incubation, followed by the occurrence of erythroid differentiation in K562 after 72 hr incubation, evidenced by the significantly upregulated CD235a and benzidine staining, which was not detectable with r-As4S4. The ee-As4S4-induced erythroid differentiation was also observed in K562/AO2 cells and bone marrow mononuclear cells of CML patients. Mechanistic studies indicated that ee-As4S4 induced autophagy by downregulating the level of intracellular ROS and hypoxia-inducible factor-1α significantly, which led to the subsequent degradation of BCR-ABL. When the concentration was increased, ee-As4S4 induced much more significant apoptosis and cell cycle arrest than r-As4S4, and the cytotoxicity of the former was about 178 times of the latter. Conclusion: ee-As4S4 was capable of inducing significant erythroid differentiation of CML cells by inducing the direct degradation of BCR-ABL; the new effect could improve hematopoietic function of CML patients as well as inhibit the leukemic cell proliferation.


Assuntos
Arsenicais/farmacologia , Diferenciação Celular/efeitos dos fármacos , Composição de Medicamentos , Células Eritroides/citologia , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Nanopartículas/química , Proteólise/efeitos dos fármacos , Sulfetos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células Eritroides/efeitos dos fármacos , Células Eritroides/ultraestrutura , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Anticancer Res ; 39(8): 4095-4100, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366493

RESUMO

BACKGROUND/AIM: Ethacridine is used as a topical antiseptic as well as for second-trimester abortion. Recent studies showed that ethacridine is an inhibitor of poly(ADP-ribose) glycohydrolase (PARG) and an activator of the transcriptional coactivator with PDZ-binding motif (TAZ). This study examined the effects of ethacridine on thyroid cancer cells. MATERIALS AND METHODS: Thyroid cancer cell lines (FTC133 and SW1736) and thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with ethacridine. Viability, clonogenicity, cell-cycle distribution, and apoptosis were evaluated. The expression of thyroid differentiation markers (TTF-1, PAX8, and NIS) was determined by real-time PCR. RESULTS: Ethacridine suppressed cell growth and clonogenic ability of thyroid cancer cells in a time- and dose-dependent manner (p<0.001). No cell-cycle arrest was found, but ethacridine dose-dependently induced apoptosis of thyroid cancer cells (p<0.001). The PAX8 and NIS expressions were significantly increased in SW1736 (3.41-fold and 1.53-fold, respectively) and Nthy-ori 3-1 cells (2.73-fold and 4.12-fold, respectively). CONCLUSION: Ethacridine elicits apoptotic cell death in thyroid cancer cells and promotes differentiation in a subset of thyroid follicular cells.


Assuntos
Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Etacridina/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Transcrição PAX8/genética , Simportadores/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Fator Nuclear 1 de Tireoide/genética
16.
Inorg Chem ; 58(16): 11076-11084, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31393117

RESUMO

Platinum drugs including cisplatin are widely used in clinics to treat various types of cancer. However, the lack of cancer-cell selectivity is one of the major problems that lead to side effects in normal tissues. Luteinizing hormone-releasing hormone (LHRH) receptors are overexpressed in many types of cancer cells but rarely presented in normal cells, making LHRH receptor a good candidate for cancer targeting. In this study, we report the synthesis and cytotoxic study of a novel platinum(IV) anticancer prodrug functionalized with LHRH peptide. This LHRH-platinum(IV) conjugate is highly soluble in water and quite stable in a PBS buffer. Cytotoxic study reveals that the prodrug selectively targets LHRH receptor-positive cancer cell lines with the cytotoxicities 5-8 times higher than those in LHRH receptor-negative cell lines. In addition, the introduction of LHRH peptide enhances the cellular accumulation in a manner of receptor-mediated endocytosis. Moreover, the LHRH-platinum(IV) prodrug is proved to kill cancer cells by binding to the genomic DNA, inducing apoptosis, and arresting the cell cycle at the G2/M phase. In summary, we report a novel LHRH-platinum(IV) anticancer prodrug having largely improved selectivity toward LHRH receptor-positive cancer cells, relative to cisplatin.


Assuntos
Antineoplásicos/farmacologia , Platina/farmacologia , Pró-Fármacos/farmacologia , Receptores LHRH/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta à Radiação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Platina/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Receptores LHRH/metabolismo , Relação Estrutura-Atividade
17.
Adv Exp Med Biol ; 1165: 233-252, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399968

RESUMO

The renal tubules are the major component of the kidney and are vulnerable to a variety of injuries including ischemia, proteinuria, toxins, and metabolic disorders. It has long been believed that tubules are the victim of injury. In this review, we shift this concept to renal tubules as a driving force in the progression of kidney disease. In response to injury, tubular epithelial cells (TECs) can synthesize and secrete varieties of bioactive molecules that drive interstitial inflammation and fibrosis. Innate immune-sensing receptors on the TECs also aggravate immune responses. Necroinflammation, an auto-amplification loop between tubular cell death and interstitial inflammation, leads to the exacerbation of renal injury. Furthermore, TECs also play an active role in progressive renal injury via mechanisms associated with the conversion into collagen-producing fibroblast phenotype, cell cycle arrest at both G1/S and G2/M checkpoints, and metabolic disorder. Thus, a better understanding the mechanisms by which tubular injury drives AKI and CKD is necessary for the development of therapeutics to halt the progression of CKD.


Assuntos
Células Epiteliais/patologia , Nefropatias/fisiopatologia , Túbulos Renais/citologia , Pontos de Checagem do Ciclo Celular , Fibrose , Humanos , Imunidade Inata , Rim/patologia
18.
Expert Opin Investig Drugs ; 28(9): 771-785, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31449760

RESUMO

Introduction: Molecular analyzes including molecular descriptor/phenotype interactions have led to better characterization of epithelial ovarian cancer patients, including a definition of a BRCA wild-type (BRCAwt) phenotype. Understanding how and when to use agents targeted against dependent BRCAwt pathways or other molecular events at disease progression is an important translational and therapeutic direction in ovarian cancer research. Areas covered: In this overview, we provide definitions and descriptions of a BRCAwt genotype and phenotype. We discuss novel investigational drugs that hold promise for the treatment of BRCAwt ovarian cancer, including inhibitors of poly(ADP-ribose) polymerase, ribonucleotide reductase, DNA protein kinase-catalytic subunit, ataxia-telangiectasia-mutated kinase (ATM), ataxia-telangiectasia mutated and Rad3-related kinase (ATR), CHK 1/2, cyclin kinases, glutaminase-1, WEE1 kinase, as well as tumor microenvironment and angiogenesis inhibitors. This article explores the known and the emerging areas of clinical research on patients with BRCAwt ovarian cancer. Expert opinion: Discovery of molecular changes tied to annotated disease information, along with an expanding array of pathway targets and targeted therapeutic agents, creates optimism and opportunity for women with ovarian cancer. Using precision oncology approaches, clinical researchers are, and will be, poised to select more effective treatments for ovarian cancer patients.


Assuntos
Antineoplásicos/farmacologia , Terapia de Alvo Molecular , Neoplasias Ovarianas/tratamento farmacológico , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Drogas em Investigação/farmacologia , Feminino , Humanos , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
19.
Cell Prolif ; 52(5): e12615, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31310044

RESUMO

OBJECTIVES: It has been widely reported that long non-coding RNAs (lncRNAs) can participate in multiple biological processes of human cancers. lncRNA HLA complex group 11 (HCG11) has been reported in human cancers as a tumour suppressor. This study focused on investigating the function and mechanism of HCG11 in glioma. MATERIALS AND METHODS: Based on The Cancer Genome Atlas (TCGA) data set and qRT-PCR analysis, the expression pattern of HCG11 was identified in glioma samples. The mechanism associated with HCG11 downregulation was determined by mechanism experiments. Gain-of-function assays were conducted for the identification of HCG11 function in glioma progression. Mechanism investigation based on the luciferase reporter assay, RIP assay and pull-down assay was used to explore the downstream molecular mechanism of HCG11. The role of molecular pathway in the progression of glioma was analysed in accordance with the rescue assays. RESULTS: HCG11 was expressed at low level in glioma samples compared with normal samples. FOXP1 could bind with HCG11 and transcriptionally inactivated HCG11. Overexpression of HCG11 efficiently suppressed cell proliferation, induced cell cycle arrest and promoted cell apoptosis. HCG11 was predominantly enriched in the cytoplasm of glioma cells and acted as a competing endogenous RNAs (ceRNAs) by sponging micro-496 to upregulate cytoplasmic polyadenylation element binding protein 3 (CPEB3). CEPB3 and miR-496 involved in HCG11-mediated glioma progression. CONCLUSIONS: HCG11 inhibited glioma progression by regulating miR-496/CPEB3 axis.


Assuntos
Glioma/patologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Antagomirs/metabolismo , Apoptose , Pontos de Checagem do Ciclo Celular , Linhagem Celular , Movimento Celular , Proliferação de Células , Progressão da Doença , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Glioma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Interferência de RNA , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo
20.
Vet Microbiol ; 235: 151-163, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31282373

RESUMO

This study demonstrates that the Muscovy duck reovirus (MDRV) p10.8 protein is one of many viral non-structural proteins that induces both cell cycle arrest and apoptosis. The p10.8 but not σC is a nuclear targeting protein that shuttles between the nucleus and the cytoplasm. Our results reveal that p10.8-induced apoptosis in cultured cells occurs by the nucleoporin Tpr/p53-dependent and Fas/caspase 8-mediated pathways. Furthermore, a compelling finding from this study is that the p10.8 and σC proteins of MDRV facilitate CDK2 and CDK4 degradation via the ubiquitin-proteasome pathway. We found that depletion of Cdc20 reversed the p10.8- and σC- mediated CDK4 degradation and p10.8-induced apoptosis, suggesting that Cdc20 plays a critical role in modulating p10.8-mediated cell cycle and apoptosis. Furthermore, we found that depletion of chaperonin-containing tailless complex polypeptide 1 (CCT) 2 and CCT5 reduced the level of Cdc20 and reversed the p10.8- and σC-mediated CDK4 degradation and p10.8-induced apoptosis, indicating that molecular chaperone CCT2 and CCT5 are required for stabilization of Ccd20 for mediating both cell cycle arrest and apoptosis. This study provides mechanistic insights into how p10.8 induces both cell cycle arrest and apoptosis.


Assuntos
Proteínas Cdc20/metabolismo , Chaperonina com TCP-1/metabolismo , Orthoreovirus/genética , Doenças das Aves Domésticas/virologia , Infecções por Reoviridae/veterinária , Proteínas não Estruturais Virais/metabolismo , Animais , Apoptose , Caspase 8/genética , Caspase 8/metabolismo , Proteínas Cdc20/genética , Pontos de Checagem do Ciclo Celular , Linhagem Celular , Cercopithecus aethiops , Chaperonina com TCP-1/genética , Patos/virologia , Fibroblastos/virologia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , RNA Interferente Pequeno , Células Vero , Proteínas não Estruturais Virais/genética
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