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1.
Beijing Da Xue Xue Bao Yi Xue Ban ; 52(5): 902-906, 2020 Oct 18.
Artigo em Chinês | MEDLINE | ID: mdl-33047727

RESUMO

OBJECTIVE: To investigate the effects of salinomycin on the proliferation and apoptosis of oral squamous carcinoma cells and to further understand the mechanisms of these effects. METHODS: The human oral squamous carcinoma cell line CAL-27 was cultured in different concentrations of salinomycin and cisplatin. After co-culture with 0, 1, 2, 4, 8, 16 and 32 µmol/L salinomycin or 0, 1.25, 2.5, 5, 10, 20, 40 and 80 µmol/L cisplatin for 24 hours and 48 hours, the proliferation of oral squamous carcinoma cells were detected by cell counting kit-8(CCK-8) assay. After being exposed to 0, 2, 4, 8 µmol/L salinomycin and 0, 5, 10, 20 µmol/L cisplatin for 48 hours, the cell cycle of oral squamous carcinoma cells was detected by flow cytometry assay, and Western blot analysis was performed to analyze the expressions of cysteine-containing aspartate-specific proteases-3(Caspase-3), cysteine-containing aspartate-specific proteases-9(Caspase-9), poly ADP-ribose polymerase (PARP), protein kinase B (Akt) and phosphorylated protein kinase B (p-Akt) protein in oral squamous carcinoma cells. RESULTS: Both salinomycin and cisplatin significantly inhibited the proliferation of oral squamous cell carcinoma CAL-27 cells in a time- and dose-dependent manner. However, compared with the first-line chemotherapeutic drug cisplatin, salinomycin showed stronger anti-proliferation activity in oral squamous carcinoma cells than cisp-latin (P < 0.001). After being exposed to 8 µmol/L salinomycin, CAL-27 cells exhibited markedly higher proportion in quiescent/ first gap phases (40.40%±1.99% vs. 64.46%±0.90%, P < 0.05), and had a significantly lower proportion in synthesis phases and second gap / mitosis phases (24.32%±2.30% vs. 18.73%±0.61%, P < 0.05; 35.01%±1.24% vs. 16.54%±1.31%, P < 0.05) compared with the dimethyl sulfoxide control group; moreover cisplatin didn't show cell-cycle specific effect on CAL-27. Western blot proved that salinomycin could up-regulate the expressions of Caspase-3 and Caspase-9 protein in oral squamous cell carcinoma CAL-27 cells (P < 0.05). At the same time, the levels of PARP, Akt and p-Akt protein were down-regulated (P < 0.05). CONCLUSION: Compared with cisplatin, salinomycin has a better inhibitory effect on the proliferation of oral squamous carcinoma cells and blocks the cell cycle process at the quiescent / first gap phase. At the same time, salinomycin could trigger apoptosis of oral squamous carcinoma cells and the mechanism is associated with the Akt/p-Akt signaling pathway.


Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias Bucais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Bucais/tratamento farmacológico , Piranos
2.
Indian J Cancer ; 57(4): 481-484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33078758

RESUMO

Worldwide, hospitals are facing problems in managing cancer patients during the ongoing COVID-19 pandemic. Given the immense cancer burden of oral cancer in India, scheduling surgeries are becoming increasingly difficult. Upfront surgeries are recommended for curative treatment of oral cancers and postponing them raises the fear of progression. Metronomic chemotherapy can be considered during the waiting period given its potential oncological benefits and ease of administration without much toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Infecções por Coronavirus/complicações , Neoplasias Bucais/tratamento farmacológico , Pandemias , Pneumonia Viral/complicações , Administração Metronômica , Protocolos de Quimioterapia Combinada Antineoplásica/provisão & distribução , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Humanos , Índia/epidemiologia , Neoplasias Bucais/complicações , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/virologia , Procedimentos Cirúrgicos Bucais , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia
3.
Int J Nanomedicine ; 15: 7651-7666, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116493

RESUMO

Introduction: Plants have always been a significant source of natural active components with biological properties. Celery seed oil (extracted from Apium graveolens) has several potential applications, but its therapeutic uses in the form of nanoemulsion formulation need to be investigated further in order to meet the demand in cancer treatment, and to alleviate the prevailing crisis arising from increased antimicrobial resistance. Methods: The therapeutic potential of celery seed oil was investigated through the formulation and testing of a nanoemulsion developed with Tween 80 (a non-ionic surfactant) and the utilization of an ultrasonication technique. Anticancer and apoptotic properties of the formulation were evaluated through MTT and Annexin V-FITC assays. The clonogenic assay aided in the identification of the antiproliferative properties of the formulation on oral squamous cell carcinoma. The antimicrobial study was supported by agar well diffusion assay, membrane integrity test and scanning electron microscopy. Results: Experiments identified relevant parameters, including optimal surfactant concentration and emulsification time. GC-MS analysis identified various components in the celery oil, but not their biological activities. A sonication time of 20 min resulted in a droplet diameter of 23.4 ± 1.80 nm. The IC50 concentration of the optimal nanoemulsion formulation against SAS cells was 1.4 µL/mL. At this concentration, cell proliferation was significantly reduced through inhibition of the anchorage-independent cell growth by disrupting colony formation and inducing cell death (apoptosis) of cancer cells. The nanoemulsion was also treated with a microbial suspension of S. aureus, and displayed antibacterial properties through lipid membrane fusion, causing cytoplasmic leakage as verified through agar well diffusion and membrane permeability assays. Scanning electron microscopy revealed complete distortion of the bacterial pathogen. Conclusion: The results in this study present celery as a possible constituent for cancer therapeutics and as a candidate for aggressive, yet safe cancer treatment. The celery-based nanoemulsion has the potential to act as a key alternative to standard antibiotic therapy.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Apium/química , Emulsões/química , Nanopartículas/química , Óleos Voláteis/farmacologia , Sonicação , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Clonais , Composição de Medicamentos , Difusão Dinâmica da Luz , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Testes de Sensibilidade Microbiana , Neoplasias Bucais/tratamento farmacológico , Nanopartículas/ultraestrutura , Óleos Voláteis/uso terapêutico , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/ultraestrutura , Tensoativos/química
4.
Anticancer Res ; 40(9): 4885-4894, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878776

RESUMO

AIM: The aim of this study was to investigate the antitumor potential of guaiazulene-3-carboxylate derivatives against oral malignant cells. MATERIALS AND METHODS: Twelve guaiazulene-3-carboxylate derivatives were synthesized by introduction of either with alkyl group [1-5], alkoxy group [6, 7], hydroxyl group [8, 9] or primary amine [10-12] at the end of sidechains. Tumor-specificity (TS) was calculated by the ratio of mean 50% cytotoxic concentration (CC50) against 3 human oral mesenchymal cell lines to that against 4 human oral squamous cell carcinoma (OSCC) cell lines. Potency-selectivity expression (PSE) was calculated by dividing TS value by CC50value against OSCC cell lines. Cell cycle analysis was performed by cell sorter. RESULTS: [6, 7] showed the highest TS and PSE values, and induced the accumulation of both subG1 and G2/M cell populations in HSC-2 OSCC cells. Quantitative structure-activity relationship analysis demonstrated that their tumor-specificity was correlated with chemical descriptors that explain the 3D shape, electric state and ionization potential. CONCLUSION: Alkoxyl guaiazulene-3-carboxylates [6, 7] can be potential candidates of lead compound for developing novel anticancer drugs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Azulenos/química , Azulenos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Azulenos/síntese química , Carcinoma de Células Escamosas/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias Bucais/patologia , Relação Quantitativa Estrutura-Atividade , Sesquiterpenos de Guaiano/síntese química
6.
J Oral Maxillofac Surg ; 78(10): 1871.e1-1871.e23, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32640209

RESUMO

PURPOSE: The purpose of this project was to investigate the expression of ß-adrenergic receptors in oral squamous cell carcinoma (OSCC) and the tumor suppressive activity of ß2-adrenergic receptor (ß2-AR) blockade. MATERIALS AND METHODS: Samples of 15 normal oral mucosal epithelial tissues, 60 surgically resected OSCC tissues, and 60 adjacent para-carcinoma tissues were collected. The expression of ß1-adrenergic receptor and ß2-AR was detected by real-time quantitative polymerase chain reaction and the Western blot test. SCC9 and Cal27 cell lines and primary OSCC cells also were included and treated with ICI-118,551 (MedChemExpress, Monmouth Junction, NJ), a selective ß2-AR blocker. In addition, the Cal27 cell line was treated with propranolol (a nonselective ß-adrenergic receptor blocker) to verify the suppressive effect of ß2-AR blockade. For in vivo assays, Cal27 cells were subcutaneously injected in the tongue flank of nude mice. ICI-118,551 was orally administered to the mice in the treatment group daily. High-throughput sequencing was used to screen for changes in gene expression. RESULTS: Real-time quantitative polymerase chain reaction and the Western blot test both showed that ß1-adrenergic receptor and ß2-AR were overexpressed in OSCC tissues and cells. A relationship was found between ß2-AR and a more advanced clinical stage, as well as preoperative lymphatic metastasis. After treatment with ICI-118,551 or propranolol, the capacities for proliferation, invasion, and metastasis of OSCC cells were significantly inhibited. Tumor size was significantly different between the ICI-118,551 and control groups. The survival time in the ICI-118,551 group also was prolonged significantly. Moreover, high-throughput sequencing identified 19 affected signaling pathways, including mitogen-activated protein kinase and PI3K-Akt. We confirmed a significant change to the expression of several genes closely related to the progression of cancer. CONCLUSION: This study showed that ß2-AR is related to a more advanced clinical stage and preoperative lymphatic metastasis. Additionally, a ß2-AR blocker has a significant suppressive effect in OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Camundongos , Camundongos Nus , Neoplasias Bucais/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Receptores Adrenérgicos beta , Receptores Adrenérgicos beta 2/genética
7.
Gene ; 757: 144936, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32640301

RESUMO

Oral squamous cell carcinoma (OSCC) accounts for nearly 90 percent of oral cavity malignancies and is one of the most widespread oral cancers in the world. The microRNAs (miRNAs or miRs) have an important role in cellular processes comprising cell cycle, differentiation, and also apoptosis. MiRNAs are also implicated in the progression of cancers, including OSCC, through a variety of signaling pathways. One of the most significant signaling pathways in OSCC is the PI3K / Akt pathway that has been illustrated to be under the tight regulation of miRNAs. Deregulation or activation of the PI3K / Akt pathway due to mutations has been revealed to be implicated in the development of oral cancer. According to studies, more than 47% of HNSCC and around 38% of OSCC samples indicate at least one molecular alteration in this signaling pathway. The potential of miRNAs for their use as therapeutic tools in the diagnosis as well as treatment of numerous diseases have been confirmed. In the current review, we summarize miRNAs and their possible mechanisms as well as their functions in OSCC advancement and progression.


Assuntos
Carcinoma de Células Escamosas/genética , MicroRNAs/genética , Neoplasias Bucais/genética , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo
8.
Anticancer Res ; 40(7): 3685-3696, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620607

RESUMO

BACKGROUND/AIM: Although chemotherapy agents, such as oxaliplatin, cisplatin, paclitaxel and bortezomib frequently cause severe peripheral neuropathy, very few studies have reported the effective strategy to prevent this side effect. In this study, we first investigated whether these drugs show higher neuropathy compared to a set of 15 other anticancer drugs, and then whether antioxidants, such as sodium ascorbate, N-acetyl-L-cysteine, and vitamin B12 have any protective effect against them. MATERIALS AND METHODS: Rat PC12 cells were induced to differentiate into neuronal cells by repeated overlay of serum-free medium supplemented with nerve growth factor. The cytotoxic levels of anticancer drugs against four human oral squamous cell carcinoma cell lines, three normal oral cells, and undifferentiated and differentiated PC12 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Cells were sorted for apoptotic cells (distributed into subG1 phase) and cells at different stages of cell cycle (G1, S and G2/M). RESULTS: All 19 anticancer drugs showed higher cytotoxicity against PC12 compared to oral normal cells. Among them, bortezomib showed the highest cytotoxicity against both undifferentiated and differentiated PC12 cell and, committed them to undergo apoptosis. Sodium ascorbate and N-acetyl-L-cysteine, but not vitamin B12, completely reversed the cytotoxicity of bortezomib. CONCLUSION: Bortezomib-induced neuropathy might be ameliorated by antioxidants.


Assuntos
Antioxidantes/farmacologia , Bortezomib/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bortezomib/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Fator de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Síndromes Neurotóxicas/metabolismo , Células PC12 , Doenças do Sistema Nervoso Periférico/metabolismo , Ratos
9.
PLoS One ; 15(7): e0236101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32678829

RESUMO

Dysregulation of histone demethylase Jumonji-C domain-containing protein 5 (JMJD5) has been identified as a great effect on tumorigenesis. Silibinin is a commonly used anti-hepatotoxic drug and exhibits anticancer effect in various cancers. However, the antitumor mechanism between silibinin and JMJD5 in oral squamous cell carcinoma (OSCC) remains unclear. In this study, the clinical significance of JMJD5 on OSCC patients was assessed through tissue microarray. Furthermore, mice bearing patient-derived tumor xenografts (PDTXs) and tongue cancer cell lines were treated with silibinin and evaluated for tumor growth and JMJD5 expression. High expression of JMJD5 in oral cancer was significantly associated with tumor size (P = 0.0241), cervical node metastasis (P = 0.0001) and clinical stage (P = 0.0002), was associated with worse survival rate compared with that of the total cohort (P = 0.0002). Collectively the data indicate that JMJD5 expression may be suitable for detection of unfavorable prognosis in OSCC patients, based in part on its apparent role as a marker of metastasis. In addition, silibinin inhibits cancer growth in vitro and in PDTX models. Furthermore, metastasis-associated protein 1 (MTA1) could regulate the expression for JMJD5 and had a positive correlation with JMJD5. Moreover, silibinin could downregulate JMJD5 and MTA1 in oral cancer. Present study thus identifies that JMJD5 might be an essential prognostic indicator and therapeutic target against OSCC progression. In addition, silibinin is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating JMJD5 in OSCC, through a mechanism likely involving MTA1/JMJD5 axis.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Histona Desmetilases/metabolismo , Neoplasias Bucais/patologia , Proteínas Repressoras/metabolismo , Silibina/farmacologia , Transativadores/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Prognóstico , Proteínas Repressoras/genética , Taxa de Sobrevida , Transativadores/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Anticancer Res ; 40(6): 3071-3080, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487601

RESUMO

BACKGROUND/AIM: Head and neck squamous cell carcinoma affects nearly 500,000 people annually. Augmenting PPARγ functional activation is linked with multiple anti-carcinogenic processes in aerodigestive cell lines and animal models. PPARγ/RXRα heterodimers may be key partners in this activation. MATERIALS AND METHODS: CA 9-22 and NA cell lines were treated with the PPARγ agonist ciglitazone and/or the RXRα agonist 9-cis-retinoic acid. PPARγ functional activation, cellular proliferation, apoptosis activity, and phenotype were subsequently analyzed. RESULTS: Ciglitazone and 9-cis-retinoic acid independently activated PPARγ and down-regulated the carcinogenic phenotype in vitro. Combination treatment significantly augmented these effects, further decreasing proliferation (p<0.0001), and increasing PPARγ functional activation (p<0.0001), apoptosis (p<0.05), and adipocyte differentiation markers (p<0.0001). CONCLUSION: The efficacy of the combination of ciglitazone and 9-cis-retinoic acid afforded lowering treatment concentrations while maintaining desired therapeutic outcomes, optimistically supporting the feasibility and practicality of this novel treatment option.


Assuntos
Neoplasias Bucais/tratamento farmacológico , PPAR gama/metabolismo , Retinoides/uso terapêutico , Tiazolidinedionas/uso terapêutico , Humanos , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Retinoides/farmacologia , Taxa de Sobrevida , Tiazolidinedionas/farmacologia
11.
J Craniomaxillofac Surg ; 48(7): 700-705, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32522395

RESUMO

INTRODUCTION: The aim of present study is to investigate the most common infection pathogen found in the postoperative wounds, following surgical treatment of oral and oropharyngeal cancer, in order to identify the most suitable antibiotic treatment. PATIENTS AND METHODS: We analyzed patients with squamous cell cancer of oral and oropharyngeal region. In patients who developed postoperative wound infection, wound swabs were taken from three different sites: the cannula, wounds on the neck and wounds in the oral cavity. RESULTS: In total 195 patients were included. The postoperative wound infection was detected in 115 patients (59%). In average, the swabs were taken 8 days after the surgery. The similar bacterial species from all three sites were detected in 24 patients (12,3%). In comparison, we found that there was statistically significant difference in the bacteria abundance from all three sites (p=0,031). There were significantly more bacteria in the wounds of the neck than cannula (p=0,007) and in the wounds in the oral cavity than cannula (p=0,002). No statistically significant difference between the wound on the neck and in the oral cavity was found. The most frequently isolated bacterial family was Enterobacteriaceae. Other more commonly isolated bacteria species were Staphylococcus spp. (G+), Pseudomonas aeruginosa (G-), Corynebacteruim spp. (G +) and Acinetobacter baumanii (G-). CONCLUSION: Based on the most commonly isolated groups of pathogens we concluded that probably the best empiric antibiotic treatment of wound infections until antibiogram is completed might be achieved from the group of aminoglycosides or quinolones. Antibiotic therapy should be reviewed if necessary when antibiogram is completed.


Assuntos
Neoplasias Bucais/tratamento farmacológico , Infecção dos Ferimentos/tratamento farmacológico , Antibacterianos/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa , Infecção da Ferida Cirúrgica/tratamento farmacológico
12.
Arch Oral Biol ; 116: 104774, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32470830

RESUMO

OBJECTIVES: The aim of the present study was to identify the anticancer effects and the mechanisms of action of shikonin and its analogue isobutyrylshikonin in oral squamous carcinoma cells. DESIGNS: The cytotoxic effects of isobutyrylshikonin and shikonin in Ca9-22 and SCC-25 cells were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry analysis of Annexin V/Propidium Iodide (PI) staining, western blot analysis and immunohistochemistry. RESULTS: Treatment with both isobutyrylshikonin and shikonin induced dose- and time-dependent apoptotic cell death in Ca9-22 cells, although the IC50 of isobutyrylshikonin was less than that of shikonin. The induction of apoptosis by both isobutyrylshikonin and shikonin was accompanied by activation of caspase-8, -9, -3, and PARP, loss of mitochondrial trans-membrane potential, and release of cytochrome c from the mitochondria. ROS mediated the apoptosis induced by isobutyrylshikonin and shikonin, indicating that ROS may play a critical role in the distinctive cytotoxic effects of isobutyrylshikonin and shikonin in Ca9-22. Isobutyrylshikonin showed a similar cytotoxic effect in SCC-25 cells at concentrations showing the effects in Ca9 cells, but not in human normal keratinocyte cells. Although there is no biological difference between isobutyrylshikonin and shikonin, isobutyrylshikonin exerts the same cytotoxic effect at a concentration 6 times lower than shikonin. CONCLUSIONS: The present study suggest that isobutyrylshikonin may be a more potent chemotherapeutic agent against oral cancer cells than shikonin. In addition, our data exhibit that both isobutyrylshikonin and shikonin induce caspase-dependent apoptosis via the mitochondrial pathway through accumulation of ROS in oral squamous carcinoma cells.


Assuntos
Neoplasias Bucais , Naftoquinonas , Apoptose , Linhagem Celular Tumoral , Humanos , Potencial da Membrana Mitocondrial , Neoplasias Bucais/tratamento farmacológico , Naftoquinonas/farmacologia , Naftoquinonas/toxicidade , Espécies Reativas de Oxigênio , Células Tumorais Cultivadas
13.
Cancer Sci ; 111(7): 2385-2399, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32385953

RESUMO

The tumor microenvironment (TME) consists of various components including cancer cells, tumor vessels, cancer-associated fibroblasts (CAFs), and inflammatory cells. These components interact with each other via various cytokines, which often induce tumor progression. Thus, a greater understanding of TME networks is crucial for the development of novel cancer therapies. Many cancer types express high levels of TGF-ß, which induces endothelial-to-mesenchymal transition (EndMT), leading to formation of CAFs. Although we previously reported that CAFs derived from EndMT promoted tumor formation, the molecular mechanisms underlying these interactions remain to be elucidated. Furthermore, tumor-infiltrating inflammatory cells secrete various cytokines, including TNF-α. However, the role of TNF-α in TGF-ß-induced EndMT has not been fully elucidated. Therefore, this study examined the effect of TNF-α on TGF-ß-induced EndMT in human endothelial cells (ECs). Various types of human ECs underwent EndMT in response to TGF-ß and TNF-α, which was accompanied by increased and decreased expression of mesenchymal cell and EC markers, respectively. In addition, treatment of ECs with TGF-ß and TNF-α exhibited sustained activation of Smad2/3 signals, which was presumably induced by elevated expression of TGF-ß type I receptor, TGF-ß2, activin A, and integrin αv, suggesting that TNF-α enhanced TGF-ß-induced EndMT by augmenting TGF-ß family signals. Furthermore, oral squamous cell carcinoma-derived cells underwent epithelial-to-mesenchymal transition (EMT) in response to humoral factors produced by TGF-ß and TNF-α-cultured ECs. This EndMT-driven EMT was blocked by inhibiting the action of TGF-ßs. Collectively, our findings suggest that TNF-α enhances TGF-ß-dependent EndMT, which contributes to tumor progression.


Assuntos
Transição Epitelial-Mesenquimal , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Biomarcadores , Fibroblastos Associados a Câncer/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular , Células Cultivadas , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , NF-kappa B/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Microambiente Tumoral/genética , Fator de Necrose Tumoral alfa/farmacologia
14.
Anticancer Res ; 40(5): 2467-2474, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366390

RESUMO

BACKGROUND/AIM: The hormonally-active form of vitamin D, 1,25(OH)2D3, demonstrated activity against oral squamous cell carcinoma (OSCC). Cytochrome P450scc (CYP11A1)-derived vitamin D hydroxyderivatives, such as 20(OH)D3 and 1,20(OH)2D3, have overlapping beneficial effects with 1,25(OH)2D3 without causing hypercalcemia. This study sought to determine (i) whether 20(OH)D3 and 1,20(OH)2D3 exhibit antitumor effects against OSCC comparable to those of 1,25(OH)2D3 and (ii) whether these effects may stem from down-regulation of sonic hedgehog (SHH) or WNT/ß-catenin signaling pathways. MATERIALS AND METHODS: Effects on CAL-27 cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt and spheroid assays. Signaling pathways were assessed by immunofluorescence and western blotting. RESULTS: 20(OH)D3 and 1,20(OH)2D3 inhibited the growth of CAL-27 and demonstrated inhibition of WNT/ß-catenin and the SHH signaling as evidenced by down-regulation of nuclear translocation of glioma-associated oncogene 1(GLI1) and ß-catenin. CONCLUSION: Noncalcemic vitamin D hydroxyderivatives demonstrated antitumor activities against OSCC comparable to those of 1,25(OH)2D3 Their activities against SHH and the WNT/ß-catenin pathways provide insight for a possible target for OSCC treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Proteínas Hedgehog/metabolismo , Neoplasias Bucais/metabolismo , Vitamina D/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Biomarcadores , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Núcleo Celular , Imunofluorescência , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/etiologia , Neoplasias Bucais/patologia , Transporte Proteico , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , beta Catenina/metabolismo
16.
Gulf J Oncolog ; 1(32): 12-28, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32342913

RESUMO

INTRODUCTION: A phase II study was conducted in patients, unsuited for surgery, with locally advanced squamous cell carcinoma of oral cavity (stage III or IV) and without distant metastasis. The objectives were to evaluate overall response (OR) rate and safety of subjects treated with induction regimen docetaxel and cisplatin, followed by definitive chemoradiotherapy (CRT) in this setting. METHODS AND MATERIALS: Induction regimen consisted of docetaxel 75mg/m2 and cisplatin 75mg/m2 on day 1; cycles repeated every 21 days for three cycles with supportive G-CSF treatment beginning at first cycle. Definitive CRT consisted of weekly cisplatin 30mg/m2 for four weeks starting concomitantly with 60 Gy/30 fractions of conventional radiotherapy for six weeks. Primary and secondary efficacy criteria were OR rate at three weeks after cycle three and eight weeks after last cycle of CRT respectively. RESULTS: Three centers enrolled 35 patients. Primary efficacy endpoint: OR rate of evaluable patients after induction (n=27) was 88.9% (95% CI:71.9-96.2). Complete response (CR) was not achieved by any patient; partial response (PR) was achieved by 88.9% (24/27). From intent to treat (ITT) analysis OR rate was 68.6% (24/35). Secondary efficacy endpoint: OR rate of evaluable patients after definitive CRT (n=19) was 78.9%(95%CI:56.7-91.5) with CR and PR achieved by 2(10.5%) and 13(68.4%) patients respectively. From ITT analysis CR rate was 5.7% (2/35) and OR rate was 42.9% (15/35). During induction most common hematological toxicity was leukopenia in eight patients, with =Grade 3 leukopenia reported in three patients. During CRT most common adverse events were alopecia, stomatitis and nausea. CONCLUSION: We observed an ITT response rate of 68.6% with induction regimen docetaxel plus cisplatin, with a manageable safety profile. Hence, further investigation in this setting is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , Indução de Remissão/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Docetaxel/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Cell Prolif ; 53(4): e12786, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32301195

RESUMO

OBJECTIVES: Photodynamic therapy (PDT) is a novel non-invasive therapeutic method, which has been widely applied for the treatment of human oral cancers. However, the problems of undesirable singlet oxygen (1 O2 ) quantum yields and long-term phototoxicity were inevitable during the application of traditional photosensitizers. Therefore, it is necessary to explore novel photosensitizers for the improvement of therapeutic effects. In our study, the sulphur-doped carbon dots (S-CDs) of high yield of singlet oxygen (1 O2 ) were synthesized as a nano-photosensitizer for OSCC to improve the PDT efficacy in clinical practice. MATERIALS AND METHODS: After synthesis of the novel S-CDs, the size, morphologic characteristics, surface potential and yield of singlet oxygen (1 O2 ) were determined. In vitro study was performed to compare the therapeutic effect as well as the biocompatibility of the novel S-CDs to those of 5-ALA. Besides, possible mechanism of action was illustrated. RESULTS: After synthesis of the novel S-CDs, the size, morphologic characteristics, surface potential and yield of singlet oxygen (1 O2 ) were determined. In vitro study was performed to compare the therapeutic effect as well as the biocompatibility of the novel S-CDs to those of 5-ALA. Besides, possible mechanism of action was illustrated. CONCLUSIONS: These data from the in vitro study demonstrated the promising safety profile of the low dose (nmol/L) S-CDs, which indicated the novel S-CDs could be used as a promising photodynamic agent for oral cancer therapy.


Assuntos
Carbono/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Enxofre/farmacologia , Apoptose/efeitos dos fármacos , Carbono/química , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Neoplasias Bucais/patologia , Nanopartículas/química , Nanopartículas/ultraestrutura , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Enxofre/química
18.
BMC Cancer ; 20(1): 229, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32183719

RESUMO

BACKGROUND: Although checkpoint blockades have become widely used, the immunological impact in cancer patients, especially those with oral cavity squamous cell carcinoma (OCSCC), has not been well studied. METHODS: The present study assessed the immunological impact of anti-PD-1 (nivolumab) treatment in 10 patients with OCSCC. This involved phenotypic analyses of peripheral blood T-cell subpopulations and their expression of immune mediators prior to and following nivolumab treatment. The focus was on immunological effects of treatment without regard to possible clinical responses. RESULTS: Nivolumab caused a decline in the frequency of blood CD4+ cells but did not affect their expression of IFN-γ. However, nivolumab increased the proportion of CD4+ cells expressing the Treg-supporting factor Foxp3. Nivolumab treatment caused an increase in the proportion of CD8+ cells. While their expression of granzyme B increased, it did not attain significance. Analyses of CD8+ cell subpopulations showed nivolumab caused an increase in levels of unconventional CD8dimCD3+ T-cells. It also caused an increase in expression of granzyme B by these unconventional T-cells as well as by the conventional CD8hiCD3+ cells. The CD8hiCD3+ subpopulation also had a near-significant increase in IFN-γ expression. Treatment with nivolumab had no effect on the levels of the NK containing CD8dimCD3- subpopulation of cells or their expression of IFN-γ or granzyme B. CONCLUSIONS: These results show nivolumab causes opposing effects on CD4+ and CD8+ cell populations, with CD4+ cell levels declining but increasing the proportion of Treg cells, and unconventional CD8+ T-cell levels increasing with increased expression of immune mediators by CD8+ T-cell subpopulations.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/imunologia , Nivolumabe/uso terapêutico , Idoso , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia
19.
Arch Oral Biol ; 113: 104707, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32197133

RESUMO

OBJECTIVE: Fatty acid synthase (FASN) is overexpressed in several human cancers, including oral squamous cell carcinoma (OSCC). TVB-3166 is a recently described FASN inhibitor with antitumor effects and potential clinical relevance. The objective of this study was to evaluate the effects of TVB-3166 on OSCC cell lines. MATERIALS AND METHODS: The OSCC cell line SCC-9 modified to express ZsGreen (ZsG) (SCC-9 ZsG) and its in vivo selected metastatic derivative LN-1A were used to evaluate anticancer properties of TVB-3166. Cell viability was determined using MTT assays and proliferation determined by cell counting in a Neubauer chamber. Cell death and cell cycle progression were analyzed by Annexin V-PE/7-ADD-PerCP labeling and PI staining, respectively. Cell migration was assayed by scratch assays and cell adhesion using myogel. Production of FASN, p-AKT, CPT1-α, and epithelial-mesenchymal transition (EMT) markers were examined by Western blotting. RESULTS: TVB-3166 significantly reduced cell viability and proliferation, promoted cell cycle arrest and apoptosis, and increased adhesion to myogel in both OSCC cell lines. Finally, the drug reduced SCC-9 ZsG migration. CONCLUSION: Our results demonstrated that TVB-3166 has anticancer effects on both SCC-9 ZsG and its metastatic version LN-1A, which are worthy of investigation in preclinical models for OSCC.


Assuntos
Azetidinas/farmacologia , Carcinoma de Células Escamosas/patologia , Ácido Graxo Sintases/antagonistas & inibidores , Neoplasias Bucais/patologia , Nitrilos/farmacologia , Pirazóis/farmacologia , Apoptose , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Neoplasias Bucais/tratamento farmacológico
20.
Anticancer Res ; 40(3): 1247-1254, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132021

RESUMO

AIM: We attempted to clarify the role of Peroxisome proliferator-activated receptor γ (PPARγ) and its ligand, troglitazone (TRO) on oral squamous cell carcinoma (SCC). MATERIALS AND METHODS: The expression of PPARγ gene was examined in 47 human oral SCC tissues and two human oral SCC cell lines, CA9-22 and HSC-4. The effects of TRO on the growth and cell-cycle progression of human oral SCC cells were examined. RESULTS: PPARγ mRNA was detected in 20 of 47 oral SCC tissues and two human oral SCC cells. TRO significantly suppressed the growth of the cells, but did not induce apoptosis. CA9-22 cells treated with TRO showed an increased fraction in the G1 phase and decreased fractions in the S and G2-M phases. CONCLUSION: TRO did not induce apoptosis in oral SCC cells, but did inhibit the growth of the cells by arresting the cell cycle at G1 phase.


Assuntos
Hipoglicemiantes/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , PPAR gama/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Troglitazona/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Ligantes , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , PPAR gama/biossíntese , PPAR gama/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
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