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1.
Anticancer Res ; 41(7): 3543-3560, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230150

RESUMO

BACKGROUND/AIM: There is a lack of data concerning the surgical treatment of locally advanced squamous cell carcinoma of the uterine cervix (LACC) with neoadjuvant and adjuvant chemotherapy (NACT, ACT) as well as total mesometrial resection (TMMR). The aim of the study was to present a novel approach for treating LACC using a tumor response score for NACT. PATIENTS AND METHODS: A total of 12 patients with LACC were treated with NACT [cisplatin, ifosfamide, paclitaxel (TIP)], TMMR and ACT containing TIP. To measure the response during NACT, we scored i) the maximum tumor diameter (maxTD) in gynecological examination, ii) the MRI for radiologic maxTD, iii) the tumor volume and iv) the squamous cell carcinoma antigen before and after two applications of TIP. RESULTS: TIP reduced all score-parameters in 10 of 12 patients (p<0.005). We found a possible reduction of lymph node metastasis in 72.7%. The proposed score detected sufficient and insufficient tumor response. CONCLUSION: TIP followed by TMMR with ACT could be a possibility for patients denying radiochemotherapy. The tumor response score can detect patients with inadequate benefit from NACT.


Assuntos
Colo do Útero/efeitos dos fármacos , Colo do Útero/cirurgia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Colo do Útero/patologia , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Histerectomia/métodos , Metástase Linfática/tratamento farmacológico , Metástase Linfática/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos
2.
Magy Onkol ; 65(2): 188-195, 2021 06 03.
Artigo em Húngaro | MEDLINE | ID: mdl-34081766

RESUMO

Head and neck squamous cell carcinomas (HNSCC) take many lifes worldwide. Patients with recurrent/metastatic disease receive combination chemotherapy containing anti-EGFR antibody cetuximab. However, resistance often hurdles therapy. The mechanism is yet to unveil, although EGFR extracellular alterations and activity of c-Met signaling were accused. We investigated the effects of EGFR-vIII and EGFR-R521K on cetuximab efficacy in HNSCC in cellular, xenograft, and clinical setup. Furthermore, we investigated the efficacy of c-Met inhibition in HNSCC in vitro and in vivo. We showed that EGFR-vIII is very rare in HNSCC, while the common R521K polymorphism abolishes antibody-dependent cellular cytotoxicity and in vivo antitumor effect of cetuximab. This selectivity was not reflected in immunophenotype or survival data of HNSCC patients, suggesting a more complex mechanism behind. Interestingly, c-Met inhibitor SU11274 was more effective in cetuximab-resistant, EGFR R521K heterozygous cells and xenografts, raising the possible importance of simultaneous targeting of the two receptors.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Cetuximab/farmacologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Braz Oral Res ; 35: e063, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34076188

RESUMO

FITOPROT, which contains curcuminoids and Bidens pilosa L. extract, is an innovative mucoadhesive formulation indicated for the topical treatment of chemoradiotherapy-induced oral mucositis (OM) in patients with advanced and visible oral squamous cell carcinoma. The formulation is used as a mouthwash directly on tumor tissue of patients with advanced neoplasms, without triggering cancer cell proliferation or tumor invasiveness. Thus, the aim of this study was to evaluate the biological effects of FITOPROT on an oral squamous cell carcinoma cell line (SCC-4). The viability of SCC-4 cells was assessed after exposure to FITOPROT using MTT reduction assay. The effects of the mucoadhesive formulation on cell cycle progression and cell death parameters were evaluated using flow cytometry. In addition, the inflammatory profile of the tumor cells was evaluated using the cytometric bead array (CBA) assay. FITOPROT promoted a concentration-dependent decrease in cell viability and cell cycle arrest at the G2/M phase (p < 0.05). Mitochondrial membrane potential was also altered after exposure to the formulation (p < 0.05), in parallel with a reduction in VEGF and IL-8 production (p = 0.01 and p = 0.05, respectively). In summary, the results indicate that FITOPROT reduces SCC-4 cell viability, promotes cell cycle arrest, modulates mitochondrial membrane potential, and exhibits antiangiogenic and anti-inflammatory properties, thus indicating its potential for topical use in patients with OM and visible tumors in the mouth.


Assuntos
Bidens , Carcinoma de Células Escamosas , Neoplasias Bucais , Apoptose , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular , Proliferação de Células , Diarileptanoides , Humanos , Neoplasias Bucais/tratamento farmacológico
4.
Int J Hyperthermia ; 38(1): 939-947, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34134574

RESUMO

BACKGROUND: Hyperthermia has been reported to cause cancer stage regression, thus providing surgical opportunities in patients with unresectable tumors and improving the quality of life of patients by preserving certain organs. METHODS: A prospective open-label phase II trial was conducted to evaluate the efficacy of hyperthermia combined with induction chemotherapy in patients with locally advanced resectable oral squamous cell carcinoma (OSCC). Patients received hyperthermia combined with two cycles of 5-fluorouracil, cisplatin, and docetaxel (TPF) induction chemotherapy regimens or TPF induction chemotherapy alone, followed by radical surgery with postoperative radiotherapy. The primary endpoint was the clinical response rate of the induction chemotherapy. The secondary endpoints were overall survival (OS), disease-free survival (DFS), and toxicity. RESULTS: A total of 120 patients were enrolled, and 115 patients were included in the clinical response analysis. The clinical response rate was significantly higher in the experimental arm than in the control arm (65.45% vs. 40.00%, p = 0.0088). There were no unexpected toxicities, and hyperthermia and induction chemotherapy did not increase the perioperative morbidity rate. Moreover, there was a significant improvement in DFS, but no significant difference in OS between the two arms. In the subgroup analysis, increased OS and DFS rates were associated with patients with favorable clinical response after induction chemotherapy in the total population, experimental arm, and control arm. CONCLUSIONS: Our study demonstrates that hyperthermia combined with induction chemotherapy is associated with a high response rate and provides a new treatment option for patients with resectable stage III or IVA OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/uso terapêutico , Terapia Combinada , Fluoruracila/uso terapêutico , Humanos , Hipertermia , Quimioterapia de Indução , Neoplasias Bucais/tratamento farmacológico , Estudos Prospectivos , Qualidade de Vida , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxoides/uso terapêutico , Resultado do Tratamento
5.
J Int Med Res ; 49(5): 3000605211016206, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34044599

RESUMO

OBJECTIVE: To identify biomarkers related to esophageal squamous cell carcinoma (ESCC) prognosis by analyzing genetic variations and the infiltration levels of tumor-infiltrating lymphocytes (TILs) in patients. METHODS: The clinical features of 61 patients with ESCC were collected. DNA panel sequencing was performed to screen differentially expressed genes (DEGs). Transcriptome sequencing was performed to identify gene expression profiles, and subsequent enrichment analysis of DEGs was conducted using Metascape. RESULTS: We identified 488 DEGs between patients with ESCC with distinct prognoses that were mainly enriched in the human immune response, fibrinogen complex, and protein activation cascade pathways. Among patients with ESCC treated with postoperative chemotherapy, those with a high infiltration level of myeloid-derived suppressor cells (MDSCs) had longer overall survival (OS), and OS was positively correlated with the infiltration level of T helper type 2 (Th2) cells among patients treated without chemotherapy after surgery. Additionally, in the case of MDSCs >0.7059 or Th2 cells <0.6290, patients receiving postoperative chemotherapy had a longer OS than those treated without chemotherapy following surgery. CONCLUSION: The level of MDSCs or Th2 cells can be used as a biomarker for assessing the prognosis of patients with ESCC treated with or without postoperative chemotherapy, respectively.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral , Prognóstico
6.
Zhonghua Zhong Liu Za Zhi ; 43(5): 569-573, 2021 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-34034477

RESUMO

Objective: To investigate the prognostic factors associated with unresectable (stage Ⅲa-Ⅳ, according to the 7th edition of the AJCC cancer staging manual) lung squamous cell carcinoma. Methods: We retrospectively analyzed 350 patients with inoperable locally advanced, recurrent or metastatic lung squamous cell carcinoma who were admitted to the First Affiliated Hospital of Chinese Medical University from January 2005 to June 2018. The clinical pathological data, treatment and survival follow-up information of the patients were collected. Kaplan-Meier survival was used to compare the overall survival rate of different risk groups. Univariate analysis and multivariate Cox regression analysis were used to determine the independent prognostic factors. Results: A total of 350 patients were enrolled. The median overall survival (OS) of these patients was 16.7 months. Univariate analysis showed the stage, Eastern Cooperative Oncology Group(ECOG), first-line chemotherapy evaluation (RECIST version 1.1), radiation therapy, number of systemic chemotherapy lines, carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), C reactive protein (CRP), lactate dehydrogenase (LDH), whether liver, brain, boneor metastasis were associated with the OS of patients with advanced lung squamous cell carcinoma (all P<0.05). Multivariate analysis showed that ECOG score (HR=1.855, 95% CI: 1.063-3.239, P=0.030), whether underwent lung resection (HR=0.476, 95%CI: 0.302-0.751, P=0.001), first-line chemotherapy evaluation [stable disease (SD): HR=0.293, 95%CI: 0.159-0.540, P<0.001; complete response (CR)+ partial response (PR): HR=0.223, 95%CI: 0.120-0.413, P<0.001], CRP (HR=1.715, 95% CI: 1.080-2.723, P=0.042), LDH (HR=1.116, 95%CI: 0.780-1.596, P=0.002) and CEA (HR=1.855, 95%CI: 1.361-2.528, P<0.001) before chemotherapy, liver metastasis (HR=2.453, 95%CI: 1.461-4.120, P=0.001) are independent prognostic factors for patients with unresectable lung squamous cell carcinoma. Conclusion: The ECOG score, surgical treatment history, first-line chemotherapy, LDH, CEA and CRP before chemotherapy, liver metastasis are independent prognostic factors for patients with advanced lung squamous cell carcinoma.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/cirurgia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
7.
Nat Commun ; 12(1): 2581, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972544

RESUMO

While the potential of patient-derived organoids (PDOs) to predict patients' responses to anti-cancer treatments has been well recognized, the lengthy time and the low efficiency in establishing PDOs hamper the implementation of PDO-based drug sensitivity tests in clinics. We first adapt a mechanical sample processing method to generate lung cancer organoids (LCOs) from surgically resected and biopsy tumor tissues. The LCOs recapitulate the histological and genetic features of the parental tumors and have the potential to expand indefinitely. By employing an integrated superhydrophobic microwell array chip (InSMAR-chip), we demonstrate hundreds of LCOs, a number that can be generated from most of the samples at passage 0, are sufficient to produce clinically meaningful drug responses within a week. The results prove our one-week drug tests are in good agreement with patient-derived xenografts, genetic mutations of tumors, and clinical outcomes. The LCO model coupled with the microwell device provides a technically feasible means for predicting patient-specific drug responses in clinical settings.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Técnicas de Cultura de Células/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias Pulmonares/tratamento farmacológico , Organoides/efeitos dos fármacos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/instrumentação , Gefitinibe/farmacologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Organoides/citologia , Organoides/patologia , Preparações Farmacêuticas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Mater Sci Eng C Mater Biol Appl ; 124: 112073, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33947565

RESUMO

Chronic wounds are considered a silent epidemic affecting a significant fraction of the World population. Their treatment supposes a large fraction of the public spending on the health of developed countries. In chronic wounds secondary to burns, trauma, UV light radiation, and diabetes, among others, the development of squamous cell carcinoma (SCC) has been reported. If detected early, 95% of SCC are most comfortable to be treated and cured; however, 5% of advanced SCC is more dangerous and challenging to treat. It has been reported that the pH value within the wound-milieu influences indirectly and directly all biochemical reactions taking place in this process of healing. Differences in pH values between normal skin and chronic cutaneous wounds could be considered in designing and developing stimuli-responsive nanomaterials. In this work, the anticancer drug 5-fluorouracil (5-FU) inclusion on gelatin-based NPs for SCC treatment has been projected. The present work goal is to prepare and characterize physicochemical and biological properties of new therapeutic-containing NPs for the sustainable delivery of 5-FU under simulated chronic wound conditions. In vitro experiments have been performed to assess the biocompatible character of these gelatin-based NPs in terms of their hemolytic and cytotoxicity properties. Due to hyperglycemia impact on both the chronicity of the wounds and chemotherapy efficacy, cellular responses have been determined under euglycemic and hyperglycemic conditions. In vitro cytotoxicity studies have reported good selective toxicity against the A431 cell line, demonstrating that gelatin-based NPs are promising dual-responsive delivery systems to SCC targeting under simulated chronic wound conditions.


Assuntos
Carcinoma de Células Escamosas , Nanopartículas , Carcinoma de Células Escamosas/tratamento farmacológico , Fluoruracila/farmacologia , Gelatina , Humanos , Cicatrização
9.
Aging (Albany NY) ; 13(9): 12691-12709, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33973529

RESUMO

Due to its effectiveness, cancer immunotherapy has attracted widespread attention from clinicians and scientific researchers. Numerous studies have proven that effective stratification of cancer patients would promote the personalized application of immunotherapy. Therefore, we used the transcriptome data of nearly 1,000 patients with non-small cell lung cancer (NSCLC) to construct a new immune subgroup. We found that the new immune subgroup, named cluster 2, was a mixture of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and showed poor overall survival, which was further verified in the independent validation set. Immune infiltration correlation analysis showed that the Mast cell type and its status subdivisions had a predictive effect on the prognosis of NSCLC, especially in LUAD. Phenotypic analysis suggested that epithelial-mesenchymal transition (EMT) was positively correlated with immunosuppression, supporting the correlation between tumor phenotype and immune background. Although immune subtypes failed to significantly distinguish the progression-free survival (PFS) of immunotherapy patients, they showed the expected trend; the sample size needs to be further expanded for verification. In addition, some results indicated that the two cancer types, LUAD and LUSC, might require independent analyses.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/mortalidade , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Mastócitos/imunologia , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , RNA-Seq , Transcriptoma/imunologia , Evasão Tumoral/genética
10.
Drug Dev Ind Pharm ; 47(5): 711-724, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34030522

RESUMO

OBJECTIVE: Oral squamous cell carcinoma (OSCC) is a frequently occurring type of cancer leading loss of huge number of lives. Folic acid (FA) conjugated solid lipid nanoparticle (SLN) loaded paclitaxel (PTX) and ascorbic acid (AA) has been used as a novel approach in this study. METHODS: The FA conjugated SLN were prepared by following high speed homogenization and ultrasonication methods. FA conjugated SLN were used alone and in combination to evaluate their efficacy against OSCC induced animal model. FA conjugated PTX and FA conjugated AA loaded SLN were further subjected to pharmacokinetic and biodistribution. RESULTS: The FA conjugated SLN showed a biphasic drug release behavior both in in vitro as well as in vivo system. FA conjugated PTX loaded SLN and FA conjugated AA loaded SLN shows high efficiency when used in combination as compared to when used individually in vivo. FA conjugated SLN shows a better therapeutic efficacy as compared to normal drug as depicted by the observation of pharmacokinetic and biodistribution studies. CONCLUSION: The in vitro and in vivo evaluation of the FA conjugated SLN concluded with a remark that, these SLN can be effectively used in the treatment of OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Nanopartículas , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Portadores de Fármacos , Ácido Fólico , Neoplasias Bucais/tratamento farmacológico , Paclitaxel/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Distribuição Tecidual
11.
Cancer Med ; 10(10): 3224-3230, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33960701

RESUMO

BACKGROUND: First-line platinum-based therapy for advanced squamous cell carcinomas of the anal canal (SCCA) implies a risk of substantial side effects, and data on second-line treatment options are limited. Paclitaxel and Capecitabine are a well-known regimen with a moderate toxicity profile, but its efficacy has not been evaluated. METHODS: We conducted a retrospective study using Danish Hospital Registers of patients treated with Paclitaxel and Capecitabine for inoperable, recurrent, or advanced metastatic SCCA in Denmark, between January 2000 and July 2018. RESULTS: A total of 52 patients met the eligibility criteria. Median age was 60.7 years (range 42-83). Efficacy was observed, with an overall response rate in patients receiving first-line (N = 28) and second-line (N = 23) Paclitaxel and Capecitabine of 39.3% (2 with complete responses) and 17.4%, respectively. Median progression-free survival (PFS) was 4.5 months (95% CI 3.3-5.9) and 3.8 months (95% CI 2.4-5.5) with OS of 6.7 months (95% CI 5.9-8.5) and 5.9 months (95% CI 3.9-14), respectively. Performance status ≥2 and neutrophil to lymphocyte ratio ≥4 were significantly associated with a short PFS. CONCLUSION: This study recognizes Paclitaxel and Capecitabine as a potential regimen for advanced SCCA, when recommended first-line therapy is not feasible or as a potential second-line treatment after failure of platinum-based chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Capecitabina/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Paclitaxel/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Canal Anal/efeitos dos fármacos , Dinamarca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Intervalo Livre de Progressão , Estudos Retrospectivos
12.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799513

RESUMO

Squamous cell carcinomas of the lung, head and neck, esophagus, and cervix account for more than two million cases of cancer per year worldwide with very few targetable therapies available and minimal clinical improvement in the past three decades. Although these carcinomas are differentiated anatomically, their genetic landscape shares numerous common genetic alterations. Amplification of the third chromosome's distal portion (3q) is a distinguishing genetic alteration in most of these carcinomas and leads to copy-number gain and amplification of numerous oncogenic proteins. This area of the chromosome harbors known oncogenes involved in squamous cell fate decisions and differentiation, including TP63, SOX2, ECT2, and PIK3CA. Furthermore, novel targetable oncogenic kinases within this amplicon include PRKCI, PAK2, MAP3K13, and TNIK. TCGA analysis of these genes identified amplification in more than 20% of clinical squamous cell carcinoma samples, correlating with a significant decrease in overall patient survival. Alteration of these genes frequently co-occurs and is dependent on 3q-chromosome amplification. The dependency of cancer cells on these amplified kinases provides a route toward personalized medicine in squamous cell carcinoma patients through development of small-molecules targeting these kinases.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Ensaios Clínicos como Assunto , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Medicina de Precisão/métodos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Análise de Sobrevida , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/mortalidade
13.
Int J Mol Sci ; 22(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918312

RESUMO

Disulfiram (DSF), an irreversible aldehyde dehydrogenase inhibitor, is being used in anticancer therapy, as its effects in humans are known and less adverse than conventional chemotherapy. We explored the potential mechanism behind the cytotoxicity of DSF-Cu+/Cu2+ complexes in oral epidermoid carcinoma meng-1 (OECM-1) and human gingival epithelial Smulow-Glickman (SG) cells. Exposure to CuCl2 or CuCl slightly but concentration-dependently decreased cell viability, while DSF-Cu+/Cu2+ induced cell death in OECM-1 cells, but not SG cells. DSF-Cu+/Cu2+ also increased the subG1 population and decreased the G1, S, and G2/M populations in OECM-1 cells, but not SG cells, and suppressed cell proliferation in both OECM-1 and SG cells. ALDH enzyme activity was inhibited by CuCl and DSF-Cu+/Cu2+ in SG cells, but not OECM-1 cells. ROS levels and cellular senescence were increased in DSF-Cu+/Cu2+-treated OECM-1 cells, whereas they were suppressed in SG cells. DSF-Cu+/Cu2+ induced mitochondrial fission in OECM-1 cells and reduced mitochondrial membrane potential. CuCl2 increased but DSF- Cu2+ impaired oxygen consumption rates and extracellular acidification rates in OECM-1 cells. CuCl2 stabilized HIF-1α expression under normoxia in OECM-1 cells, and complex with DSF enhanced that effect. Levels of c-Myc protein and its phosphorylation at Tyr58 and Ser62 were increased, while levels of the N-terminal truncated form (Myc-nick) were decreased in DSF-Cu+/Cu2-treated OECM-1 cells. These effects were all suppressed by pretreatment with the ROS scavenger NAC. Overexpression of c-Myc failed to induce HIF-1α expression. These findings provide novel insight into the potential application of DSF-CuCl2 complex as a repurposed agent for OSCC cancer therapy.


Assuntos
Inibidores de Acetaldeído Desidrogenases/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cobre/uso terapêutico , Dissulfiram/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , Inibidores de Acetaldeído Desidrogenases/química , Inibidores de Acetaldeído Desidrogenases/farmacologia , Carcinoma de Células Escamosas/metabolismo , Cobre/química , Dissulfiram/química , Dissulfiram/farmacologia , Reposicionamento de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias/efeitos dos fármacos , Neoplasias Bucais/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/metabolismo
14.
Molecules ; 26(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807509

RESUMO

In addition to surgery, chemotherapy, radiotherapy, and targeted therapy, immunotherapy has emerged as a standard pillar of cancer treatment. Immune checkpoint inhibitors (ICIs) such as targeting programmed death-1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have been integrated into standard-of-care regimens for patients with advanced lung squamous cell carcinoma (LUSC), who were previously limited by the lack of treatment options. Atezolizumab, durvalumab, nivolumab, and pembrolizumab are all currently used as part of standard-of-care treatment for different stages of lung cancer. Recent successes and failures of immune checkpoint blockade-based combination therapies have provided significant insights into implementing combination strategies in LUSC. Therefore, there is an urgent need to correctly select patients who are more likely to respond to immunotherapy and understand the mechanisms of primary or acquired resistance. In this review, we aim at summarizing the emerging clinical data on the promise and challenge of ICIs, discussing the unmet need of potential biomarkers for predicting response or resistance to immunotherapy, and providing an overview of the current immune landscape and future directions in advanced LUSC.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Neoplasias Pulmonares/patologia
15.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808215

RESUMO

Cutaneous squamous cell carcinomas (cSCCs) account for about 20% of keratinocyte carcinomas, the most common cancer in the UK. Therapeutic options for cSCC patients who develop metastasis are limited and a better understanding of the biochemical pathways involved in cSCC development/progression is crucial to identify novel therapeutic targets. Evidence indicates that the phosphoinositide 3-kinases (PI3Ks)/Akt pathway plays an important role, in particular in advanced cSCC. Questions remain of whether all four PI3K isoforms able to activate Akt are involved and whether selective inhibition of specific isoform(s) might represent a more targeted strategy. Here we determined the sensitivity of four patient-derived cSCC cell lines to isoform-specific PI3K inhibitors to start investigating their potential therapeutic value in cSCC. Parallel experiments were performed in immortalized keratinocyte cell lines. We observed that pan PI3Ks inhibition reduced the growth/viability of all tested cell lines, confirming the crucial role of this pathway. Selective inhibition of the PI3K isoform p110α reduced growth/viability of keratinocytes and of two cSCC cell lines while affecting the other two only slightly. Importantly, p110α inhibition reduced Akt phosphorylation in all cSCC cell lines. These data indicate that growth and viability of the investigated cSCC cells display differential sensitivity to isoform-specific PI3K inhibitors.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , Humanos , Imidazóis/farmacologia , Isoenzimas , Queratinócitos/efeitos dos fármacos , Queratinócitos/enzimologia , Morfolinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Tiazóis/farmacologia , Tiazolidinedionas/farmacologia
16.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807213

RESUMO

Incidence of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis has increased worldwide, and non-steroidal anti-inflammatory drugs as celecoxib are considered for treatment. We show here strong anti-proliferative effects of celecoxib in four cSCC cell lines, while apoptosis and cell viability largely remained unaffected. Impeded apoptosis was overcome in combinations with agonistic CD95 antibody or TNF-related apoptosis-inducing ligand (TRAIL), resulting in up to 60% apoptosis and almost complete loss of cell viability. Proapoptotic caspase cascades were activated, and apoptosis was suppressed by caspase inhibition. TRAIL receptor (DR5) and proapoptotic Bcl-2 proteins (Puma and Bad) were upregulated, while anti-apoptotic factors (survivin, XIAP, cFLIP, Mcl-1, and Bcl-w) were downregulated. Strongly elevated levels of reactive oxygen species (ROS) turned out as particularly characteristic for celecoxib, appearing already after 2 h. ROS production alone was not sufficient for apoptosis induction but may play a critical role in sensitizing cancer cells for apoptosis and therapy. Thus, the full therapeutic potential of celecoxib may be better used in combinations with death ligands. Furthermore, the immune response against cSCC/AK may be improved by celecoxib, and combinations with checkpoint inhibitors, recently approved for the treatment of cSCC, may be considered.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Celecoxib/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia
17.
Ann Palliat Med ; 10(3): 3510-3517, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33849133

RESUMO

With the popularity of neoadjuvant therapy as first-line treatment, especially for advanced squamous cell carcinoma (SCC), the focus has become accurate individualized treatment. Specifically, toxic side effects of traditional platinum-doublet chemotherapy are high, so treatment with pembrolizumab plus platinum-doublet chemotherapy is safer and more effective. Pembrolizumab is a humanized monoclonal IgG4 kappa anti-PD1 antibody. It is devoid of any cytotoxic activity among the drug effect. Pembrolizumab has been tested clinically in a series of KEYNOTE studies and 12 categories of malignancies have been tested to determine their clinical effects. A 64-year-old man with IIIA SCC of the lung without any surgical contraindications in the preoperative period successfully underwent radical resection and had a great prognosis after neoadjuvant treatment. Chest computed tomography (CT) showed that the left upper lung lesion, hilar and mediastinal lymph nodes were obviously smaller than before, meanwhile, obstructive pneumonia was significantly absorbed. No sign of metastasis was detected by head-abdominopelvic CT and bone scan. Although radiation pneumonitis was an adverse event after postoperative adjuvant therapy, symptoms were relieved with low-dose glucocorticoids. In conclusion, traditional chemotherapy with single agents alone has been gradually replaced by pembrolizumab plus platinum-doublet chemotherapy as a first-line therapy now.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Pulmão , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Platina/uso terapêutico
18.
BMJ Case Rep ; 14(4)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883116

RESUMO

We report a case of periocular squamous cell carcinoma invading the anterior orbit that significantly reduced in size and regressed from invasive to in situ following treatment with oral acitretin, a second-generation retinoid. The residual in situ disease was then successfully treated with cryotherapy and the patient remains in remission 12 months following cessation of systemic acitretin.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Cutâneas , Acitretina/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Neoplasias Cutâneas/tratamento farmacológico
20.
Adv Exp Med Biol ; 1280: 219-230, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791985

RESUMO

Head and neck squamous cell carcinoma (HNSCC) glycolysis is an important factor for the advancement of the disease and metastasis. Upregulation of glycolysis leads to decreased sensitivity to chemotherapy and radiation. HNSCC cells maintain constitutive glycolytic flux generating metabolic intermediates for the synthesis of amino acids, nucleotides, and fats for cell survival and disease progression. There are several pathways such as PI3K/Akt, EGFR, and JAK-STAT that contribute a major role in metabolic alteration in HNSCC. Recent studies have demonstrated that cancer-associated fibroblasts abundant in the HNSCC tumor microenvironment play a major role in HNSCC metabolic alteration via hepatocyte growth factor (HGF)/c-Met cross signaling. Despite therapeutic advancement, HNSCC lacks broad range of therapeutic interventions for the treatment of the disease. Thus, understanding the different key players involved in glucose metabolism and targeting them would lead to the development of novel drugs for the treatment of HNSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Glicólise , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Fosfatidilinositol 3-Quinases/genética , Microambiente Tumoral
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