RESUMEN

The oral cavity is a frequent site for head and neck cancers, which rank as the sixth most common cancer globally, with a 5-year survival rate slightly over 50%. Current treatments are limited, and resistance to therapy remains a significant clinical obstacle. IsCT1, a membrane-active peptide derived from the venom of the scorpion Opisthacanthus madagascariensis, has shown antitumor effects in various cancer cell lines, including breast cancer and chronic myeloid leukemia. However, its hemolytic action limits its potential therapeutic use. This study aims to assess the antitumor and antiproliferative activities of synthetic peptides derived from IsCT1 (IsCT-P, AC-AFPK-IsCT1, AFPK-IsCT1, AC-KKK-IsCT1, and KKK-IsCT1) in the context of oral squamous cell carcinoma. We evaluated the cytotoxic effects of these peptides on tongue squamous cell carcinoma cells and normal cells, as well as their impact on cell cycle phases, the expression of proliferation markers, modulators of cell death pathways, and mitochondrial potential. Our results indicate that the IsCT1 derivatives IsCT-P and AC-AFPK-IsCT1 possess cytotoxic properties towards squamous cell carcinoma cells, reducing mitochondrial membrane potential and the proliferative index. The treatment of cancer cells with AC-AFPK-IsCT1 led to a positive modulation of pro-apoptotic markers p53 and caspases 3 and 8, a decrease in PCNA and Cyclin D1 expression, and cell cycle arrest in the S phase. Notably, contrary to the parental IsCT1 peptide, AC-AFPK-IsCT1 did not exhibit hemolytic activity or cytotoxicity towards normal cells. Therefore, AC-AFPK-IsCT1 might be a viable therapeutic option for head and neck cancer treatment.

Asunto(s)

Antineoplásicos , Carcinoma de Células Escamosas , Proliferación Celular , Neoplasias de la Boca , Venenos de Escorpión , Humanos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Venenos de Escorpión/farmacología , Venenos de Escorpión/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Péptidos/farmacología , Péptidos/química , Péptidos/síntesis química , Apoptosis/efectos de los fármacos , Escorpiones/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ciclo Celular/efectos de los fármacos

RESUMEN

OBJECTIVES: Chemoprevention can be a treatment for potentially malignant lesions (PMLs). We aimed to evaluate whether artemisinin (ART) and cisplatin (CSP) are associated with apoptosis and immunogenic cell death (ICD) in vitro, using oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) cell lines, and whether these compounds prevent OL progression in vivo. METHODS: Normal keratinocytes (HaCat), Dysplastic oral cells (DOK), and oral squamous cell carcinoma (SCC-180) cell lines were treated with ART, CSP, and ART + CSP to analyze cytotoxicity, genotoxicity, cell migration, and increased expression of proteins related to apoptosis and ICD. Additionally, 41 mice were induced with OL using 4NQO, treated with ART and CSP, and their tongues were histologically analyzed. RESULTS: In vitro, CSP and CSP + ART showed dose-dependent cytotoxicity and reduced SCC-180 migration. No treatment was genotoxic, and none induced expression of proteins related to apoptosis and ICD; CSP considerably reduced High-mobility group box-1 (HMGB-1) protein expression in SCC-180. In vivo, there was a delay in OL progression with ART and CSP treatment; however, by the 16th week, only CSP prevented progression to OSCC. CONCLUSION: Expression of proteins related to ICD and apoptosis did not increase with treatments, and CSP was shown to reduce immunogenic pathways in SCC-180, while reducing cell migration. ART did not prevent the malignant progression of OL in vivo; CSP did despite significant adverse effects.

Asunto(s)

Apoptosis , Artemisininas , Movimiento Celular , Cisplatino , Progresión de la Enfermedad , Leucoplasia Bucal , Neoplasias de la Boca , Artemisininas/farmacología , Animales , Leucoplasia Bucal/patología , Leucoplasia Bucal/tratamiento farmacológico , Humanos , Cisplatino/farmacología , Ratones , Neoplasias de la Boca/patología , Neoplasias de la Boca/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proteína HMGB1/metabolismo , Antineoplásicos/farmacología

RESUMEN

A patient presented with corneoscleral thinning five months after the treatment of suspected ocular squamous surface neoplasia with mitomycin-C and interferon. For tectonic and aesthetic purposes, we decided to perform lamellar corneoscleral transplantation. The approach used established new tectonic support and corneal homeostasis. This technique might be an option in similar cases.

Asunto(s)

Trasplante de Córnea , Mitomicina , Humanos , Mitomicina/uso terapéutico , Trasplante de Córnea/métodos , Enfermedades de la Córnea/cirugía , Enfermedades de la Córnea/tratamiento farmacológico , Neoplasias del Ojo/cirugía , Neoplasias del Ojo/tratamiento farmacológico , Neoplasias del Ojo/patología , Resultado del Tratamiento , Masculino , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Antibióticos Antineoplásicos/uso terapéutico

RESUMEN

Oral squamous cell carcinoma (OSCC) constitutes over 90% of oral cancers, known for its aggressiveness and poor prognosis. Photodynamic therapy (PDT) has emerged as a promising adjuvant therapy and is linked to immunogenic cell death, activating innate and adaptive anti-tumor responses. Natural Killer (NK) cells, key players in malignant cell elimination, have not been extensively studied in PDT. This study evaluates whether PDT increases OSCC cell lines' susceptibility to NK cell cytotoxicity. PDT, using 5-aminolevulinic acid (5-ALA) and LED irradiation, was applied to Ca1 and Luc4 cell lines. Results showed a dose-dependent viability decrease post-PDT. Gene expression analysis revealed upregulation of NK cell-activating ligands (ULBP1-4, MICA/B) and decreased MHC class I expression in Ca1, suggesting increased NK cell susceptibility. Enhanced NK cell cytotoxicity was confirmed in Ca1 but not in Luc4 cells. These findings indicate that PDT may enhance NK cell-mediated cytotoxicity in OSCC, offering potential for improved treatment strategies.

Asunto(s)

Ácido Aminolevulínico , Carcinoma de Células Escamosas , Células Asesinas Naturales , Neoplasias de la Boca , Fotoquimioterapia , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Neoplasias de la Boca/patología , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/inmunología , Línea Celular Tumoral , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/inmunología , Ácido Aminolevulínico/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Citotoxicidad Inmunológica/efectos de los fármacos

RESUMEN

OBJECTIVE: Cancer genomics and transcriptomics studies have provided a large volume of data that enables to test of hypotheses based on real data from cancer patients. Ezrin (encoded by the EZR gene) is a highly expressed protein in cancer that contributes to linking the actin cytoskeleton to the cell membrane and signal transduction pathways involved in oncogenesis and disease progression. NSC305787 is a pharmacological ezrin inhibitor with potential antineoplastic effects. In the present study, the authors prospected EZR mRNA levels in a pan-cancer analysis and identified potential cancers that could benefit from anti-EZR therapies. METHODS: This study analyzed TCGA data for 32 cancer types, emphasizing cervical squamous cell carcinoma and stomach adenocarcinoma. It investigated the impact of EZR transcript levels on clinical outcomes and identified differentially expressed genes. Cell lines were treated with NSC305787, and its effects were assessed through various cellular and molecular assays. RESULTS: EZR mRNA levels are highly expressed, and their expression is associated with biologically relevant molecular processes in cervical squamous carcinoma and stomach adenocarcinoma. In cellular models of cervical and gastric cancer, NSC305787 reduces cell viability and clonal growth (p < 0.05). Molecular analyses indicate that the pharmacological inhibition of EZR induces molecular markers of cell death and DNA damage, in addition, to promoting the expression of genes associated with apoptosis and inhibiting the expression of genes related to survival and proliferation. CONCLUSION: The present findings provide promising evidence that ezrin may be a molecular target in the treatment of cervical and gastric carcinoma.

Asunto(s)

Adenocarcinoma , Proteínas del Citoesqueleto , Perfilación de la Expresión Génica , Neoplasias Gástricas , Neoplasias del Cuello Uterino , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Proteínas del Citoesqueleto/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/metabolismo , Línea Celular Tumoral , Femenino , Adenocarcinoma/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , ARN Mensajero , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Apoptosis/genética

RESUMEN

OBJECTIVE: Treating aggressive superficial squamous cell carcinoma (SCC) poses challenges due to invasiveness. Palliative care is recommended for inoperable cases with extensive tumors near vital organs, risking disfigurement or functional impairment. Electrochemotherapy (ECT) is an emerging cutaneous tumor treatment, but its efficacy against superficial SCC remains uncertain. This study conducts a systematic review and single-arm meta-analysis to evaluate ECT's effectiveness against superficial SCC and provide current evidence for clinical practice. METHODS: Embase, PubMed and Cochrane Library were searched for studies up to May 2023. The random effects model analyzed complete response (CR) and partial response (PR), with subgroup assessment based on drug dosage, treatment response evaluation, tumor size, primary/recurrent status, and tumor location. RESULTS: Ten studies involving 162 patients and 208 tumors were included. Pooled CR and PR rates for ECT-treated superficial SCC were 66.5% (95% CI 48.4%-82.5%; I2 = 84%) and 20.3% (95% CI 10.5%-32.3%; I2 = 70%), respectively. Subgroup analysis indicated ECT's superiority in treating primary tumors (PR: 70%, CR: 30%) and tumors ≤ 3 cm (PR: 81.3%, CR: 10.1%) compared to recurrent tumors (PR: 56.7%, CR: 36.5%) and tumors > 3 cm (PR: 45.2%, CR: 34.4%). CONCLUSION: This single-arm meta-analysis confirms ECT's efficacy against superficial SCC, especially in primary tumors and those ≤ 3 cm in diameter. The study highlights the impact of tumor location and response evaluation on ECT's benefits, warranting further investigation through additional research.

Asunto(s)

Carcinoma de Células Escamosas , Electroquimioterapia , Neoplasias Cutáneas , Humanos , Electroquimioterapia/métodos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Resultado del Tratamiento

RESUMEN

UNASSIGNED: Background: Since to the prognosis of lung squamous cell carcinoma is generally poor, there is an urgent need to innovate new prognostic biomarkers and therapeutic targets to improve patient outcomes. Objectives: Our goal was to develop a novel multi-gene prognostic model linked to neutrophils for predicting lung squamous cell carcinoma prognosis. Methods: We utilized messenger RNA expression profiles and relevant clinical data of lung squamous cell carcinoma patients from the Cancer Genome Atlas database. Through K-means clustering, least absolute shrinkage and selection operator regression, and univariate/multivariate Cox regression analyses, we identified 12 neutrophil-related genes strongly related to patient survival and constructed a prognostic model. We verified the stability of the model in the Cancer Genome Atlas database and gene expression omnibus validation set, demonstrating the robust predictive performance of the model. Results: Immunoinfiltration analysis revealed remarkably elevated levels of infiltration for natural killer cells resting and monocytes in the high-risk group compared to the low-risk group, while macrophages had considerably lower infiltration in the high risk group. Most immune checkpoint genes, including programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4, exhibited high expression levels in the high risk group. Tumor immune dysfunction and exclusion scores and immunophenoscore results suggested a potential inclination toward immunotherapy in the "RIC" version V2 revised high risk group. Moreover, prediction results from the CellMiner database revealed great correlations between drug sensitivity (e.g., Vinorelbine and PKI-587) and prognostic genes. Conclusion: Overall, our study established a reliable prognostic risk model that possessed significant value in predicting the overall survival of lung squamous cell carcinoma patients and may guide personalized treatment strategies. (Rev Invest Clin. 2024;76(2):116-31).

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias Pulmonares , Neutrófilos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Pronóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/tratamiento farmacológico , Masculino , Femenino , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Anciano , Regulación Neoplásica de la Expresión Génica , ARN Mensajero/genética

RESUMEN

Head and neck squamous cell carcinoma (HNSCC) is well known as a serious health problem worldwide, especially in low-income countries or those with limited resources, such as most countries in Latin America. International guidelines cannot always be applied to a population from a large region with specific conditions. This study established a Latin American guideline for care of patients with head and neck cancer and presented evidence of HNSCC management considering availability and oncologic benefit. A panel composed of 41 head and neck cancer experts systematically worked according to a modified Delphi process on (1) document compilation of evidence-based answers to different questions contextualized by resource availability and oncologic benefit regarding Latin America (region of limited resources and/or without access to all necessary health care system infrastructure), (2) revision of the answers and the classification of levels of evidence and degrees of recommendations of all recommendations, (3) validation of the consensus through two rounds of online surveys, and (4) manuscript composition. The consensus consists of 12 sections: Head and neck cancer staging, Histopathologic evaluation of head and neck cancer, Head and neck surgery-oral cavity, Clinical oncology-oral cavity, Head and neck surgery-oropharynx, Clinical oncology-oropharynx, Head and neck surgery-larynx, Head and neck surgery-larynx/hypopharynx, Clinical oncology-larynx/hypopharynx, Clinical oncology-recurrent and metastatic head and neck cancer, Head and neck surgery-reconstruction and rehabilitation, and Radiation therapy. The present consensus established 48 recommendations on HNSCC patient care considering the availability of resources and focusing on oncologic benefit. These recommendations could also be used to formulate strategies in other regions like Latin America countries.

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , América Latina/epidemiología , Consenso , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/terapia

RESUMEN

PURPOSE: Immune checkpoint inhibitors (ICIs) for non-small-cell lung cancer (NSCLC) are on the rise, but unfortunately, only a small percentage of patients benefit from them in the long term. Thus, it is crucial to identify biomarkers that can forecast the efficacy of immunotherapy. METHODS: We retrospectively studied 224 patients with NSCLC who underwent anti-PD-1 therapy. The role of biomarkers and clinical characteristics were assessed in a prognostic model. RESULTS: Only 14.3% of patients had both programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB) outcomes, highlighting the need to investigate more available biomarkers. Our analysis found a correlation between histological PD-L1 TPS and hematological PD-1 expression. Analysis of hematological biomarkers revealed that elevated expression of CD4/CD8 and LYM% are positively associated with effective immunotherapy, while PD-1+ on T cells, NLR, and MLR have a negative impact. Moreover, high level of ΔCEA%, CYFRA21-1 and LDH may suggest ineffective ICIs. We also observed that disparate immunotherapy drugs didn't significantly impact prognosis. Lastly, by comparing squamous carcinoma and adenocarcinoma cohorts, ΔCEA%, CD3+PD-1+, CD4+PD-1+, and CD4/CD8 are more important in predicting the prognosis of adenocarcinoma patients, while age is more significant for squamous carcinoma patients. CONCLUSION: Our research has yielded encouraging results in identifying a correlation between immunotherapy's response and clinical characteristics, peripheral immune cell subsets, and biochemical and immunological biomarkers. The screened hematological detection panel could be used to forecast an NSCLC patient's response to anti-PD-1 immunotherapy with an accuracy rate of 76.3%, which could help customize suitable therapeutic decision-making.

Asunto(s)

Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/sangre , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Biomarcadores de Tumor/sangre , Anciano , Inmunoterapia/métodos , Pronóstico , Adulto , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano de 80 o más Años , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/terapia

RESUMEN

PURPOSE: Oral squamous cell carcinoma (OSCC) is commonly preceded by potentially malignant lesions, referred to as oral dysplasia. We recently reported that oral dysplasia is associated with aberrant activation of the Wnt/ß-catenin pathway, due to overexpression of Wnt ligands in a Porcupine (PORCN)-dependent manner. Pharmacologic inhibition of PORCN precludes Wnt secretion and has been proposed as a potential therapeutic approach to treat established cancers. Nevertheless, there are no studies that explore the effects of PORCN inhibition at the different stages of oral carcinogenesis. EXPERIMENTAL DESIGN: We performed a model of tobacco-induced oral cancer in vitro, where dysplastic oral keratinocytes (DOK) were transformed into oral carcinoma cells (DOK-TC), and assessed the effects of inhibiting PORCN with the C59 inhibitor. Similarly, an in vivo model of oral carcinogenesis and ex vivo samples derived from patients diagnosed with oral dysplasia and OSCC were treated with C59. RESULTS: Both in vitro and ex vivo oral carcinogenesis approaches revealed decreased levels of nuclear ß-catenin and Wnt3a, as observed by immunofluorescence and IHC analyses. Consistently, reduced protein and mRNA levels of survivin were observed after treatment with C59. Functionally, treatment with C59 in vitro resulted in diminished cell migration, viability, and invasion. Finally, by using an in vivo model of oral carcinogenesis, we found that treatment with C59 prevented the development of OSCC by reducing the size and number of oral tumor lesions. CONCLUSIONS: The inhibition of Wnt ligand secretion with C59 represents a feasible treatment to prevent the progression of early oral lesions toward OSCC.

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Vía de Señalización Wnt , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias de la Boca/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello , Carcinogénesis/genética , Aciltransferasas/metabolismo , Aciltransferasas/farmacología , Proteínas de la Membrana/metabolismo

RESUMEN

BACKGROUND: Epidermal growth factor receptor (EGFR) is frequently activated in head and neck squamous cell carcinoma (HNSCC) and serves as a valuable target for therapy. Despite the availability of the EGFR inhibitors Cetuximab, Afatinib, and Allitinib, there are limited predictive markers for their response. Understanding molecular aberrations in HNSCC could facilitate the identification of new strategies for patient clinical and biological classification, offering novel therapeutic avenues. METHODS: We assessed CCNA1, DCC, MGMT, CDKN2A/p16, and DAPK methylation status in HNSCC cell lines and their association with anti-EGFR treatment response. RESULTS: MGMT methylation status displayed high sensitivity and specificity in distinguishing sensitive and resistant HNSCC cell lines to Afatinib (AUC = 0.955) and Allitinib (AUC = 0.935). Moreover, DAPK methylation status predicted response to Allitinib with high accuracy (AUC = 0.852), indicating their putative predictive biomarker roles. CONCLUSION: These findings hold promise for the development of more personalized and effective treatment approaches for HNSCC patients.

Asunto(s)

Acrilamidas , Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Quinazolinas , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Afatinib , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Cetuximab/farmacología , Cetuximab/uso terapéutico , Receptores ErbB/metabolismo , Línea Celular Tumoral , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/uso terapéutico , Proteínas Supresoras de Tumor , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/uso terapéutico

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias Cutáneas , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología

RESUMEN

BACKGROUND: Oral squamous cell carcinoma has high recurrence and cisplatin resistance. As cancer stem cells, autophagy, and sphingolipids have been appointed as associated with chemotherapy resistance, we tested combined treatments targeting autophagy and/or sphingolipid metabolism with paclitaxel using cisplatin-resistant oral squamous cell carcinoma cells. METHODS: Cisplatin-resistant oral squamous cell carcinoma cells were maintained under exposition to FTY720 and chloroquine combined with paclitaxel and submitted to viability, clonogenicity, and spheres formation assays. The xenograft tumor model using cisplatin-resistant CAL27 cells was adopted to examine the drug combinations' potential antitumoral efficacy. Using an animal model, sphingolipids profiles from plasma and tissue samples were obtained by liquid chromatography coupled to mass spectrometry to identify potential lipids associated with drug response. RESULTS AND DISCUSSION: Our results showed higher autophagic flux in cisplatin-resistant Ooral squamous cell carcinoma (CAL27 and SCC9) cells than in parental cells. The combinations of an autophagy inhibitor (chloroquine) or an autophagy inducer/sphingosine kinase 1 antagonist (FTY720) with paclitaxel (PTX) had a synergistic antitumor effect. Treated CisR cells lost clonogenicity and tumor sphere abilities and reduced proteins associated with proliferation, survival, and cancer stem cells. FTY720 plus PTX had higher antitumor efficacy than PTX against CAL27 CisR xenograft tumor formation. Additionally, increases in glucosylceramide, dehydroglucosylceramide, and sphingomyelin were presented in responsive tumors. CONCLUSION: FTY720 sensitizes cisplatin-resistant oral squamous cell carcinoma cells for paclitaxel.

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Animales , Humanos , Cisplatino/farmacología , Paclitaxel/farmacología , Clorhidrato de Fingolimod/farmacología , Clorhidrato de Fingolimod/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello , Apoptosis , Neoplasias de la Boca/tratamiento farmacológico , Esfingolípidos/farmacología , Cloroquina/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos

RESUMEN

Tumor resistance remains an obstacle to successfully treating oral squamous cell carcinoma (OSCC). Cisplatin is widely used as a cytotoxic drug to treat solid tumors, including advanced OSCC, but with low efficacy due to chemoresistance. Therefore, identifying the pathways that contribute to chemoresistance may show new possibilities for improving the treatment. This work explored the role of the tumor necrosis factor-alpha (TNF-alpha)/NFkB signaling in driving the cisplatin resistance of OSCC and its potential as a pharmacological target to overcome chemoresistance. Differential accessibility analysis demonstrated the enrichment of opened chromatin regions in members of the TNF-alpha/NFkB signaling pathway, and RNA-Seq confirmed the upregulation of TNF-alpha/NFkB signaling in cisplatin-resistant cell lines. NFkB was accumulated in cisplatin-resistant cell lines and in cancer stem cells (CSC), and the administration of TNF-alpha increased the CSC, suggesting that TNF-alpha/NFkB signaling is involved in the accumulation of CSC. TNF-alpha stimulation also increased the histone deacetylases HDAC1 and SIRT1. Cisplatin-resistant cell lines were sensitive to the pharmacological inhibition of NFkB, and low doses of the NFkB inhibitors, CBL0137, and emetine, efficiently reduced the CSC and the levels of SIRT1, increasing histone acetylation. The NFkB inhibitors decreased stemness potential, clonogenicity, migration, and invasion of cisplatin-resistant cell lines. The administration of the emetine significantly reduced the tumor growth of cisplatin-resistant xenograft models, decreasing NFkB and SIRT1, increasing histone acetylation, and decreasing CSC. TNF-alpha/NFkB/SIRT1 signaling regulates the epigenetic machinery by modulating histone acetylation, CSC, and aggressiveness of cisplatin-resistant OSCC and the NFkB inhibition is a potential strategy to treat chemoresistant OSCC.

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos , Emetina/metabolismo , Emetina/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Histonas/metabolismo , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Células Madre Neoplásicas/patología , Sirtuina 1/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba

RESUMEN

PURPOSE: The CCR5/CCL5 axis is essential for interactions between malignant cells and microenvironment components, promoting tumor progression in oral squamous cell carcinoma (OSCC). This study aims to evaluate the association of CCL5 and CCR5 with the behavior of oral cancer and assess the therapeutic potential of a CCR5 antagonist. METHODS: A retrospective study to analyze CCR5 and CCL5 expression on paraffin-embedded tissues was performed. In cell lines, rhCCL5 was added to induce CCR5-related pathways, and Maraviroc and shRNA against CCR5 were used to neutralize the receptor. Finally, an in vivo murine orthotopic xenograft model of tongue cancer was used to evaluate Maraviroc as an oncologic therapy. After 15 days, the mice were killed, and the primary tumors and cervical lymph nodes were analyzed. RESULTS: The expression of CCR5 was associated with clinical stage and metastasis, and CCL5 was related to overall survival. Adding rhCCL5 induced cell proliferation, while shRNA and Maraviroc reduced it in a dose-dependent manner. Maraviroc treatment also increased apoptosis and modified cytoskeletal organization. In vivo, Maraviroc reduced neck metastasis. CONCLUSIONS: The effects of CCR5 antagonists in OSCC have been poorly studied, and this study reports in vitro and in vivo evidence for the effects of Maraviroc in OSCC. Our results suggest that the CCR5/CCL5 axis plays a role in oral cancer behavior, and that its inhibition is a promising new therapy alternative.

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Animales , Ratones , Maraviroc/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello , Estudios Retrospectivos , Línea Celular Tumoral , Neoplasias de la Boca/tratamiento farmacológico , ARN Interferente Pequeño/metabolismo , Microambiente Tumoral , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo

RESUMEN

OBJECTIVE: Gossypetin, isolated from Hibiscus sabdariffa L, has been shown to have various pharmacological effects including anti-inflammatory and antibacterial activity against various diseases. However, since the effect of gossypetin in oral cancer remains to be reported, we aimed to investigate the anticancer activity and mechanisms of gossypetin in oral squamous cell carcinoma (OSCC). METHODOLOGY: The proliferation of OSCC cells was evaluated by cell viability and soft agar colony assays. The effects of gossypetin on the migration and invasion of OSCC cells was investigated by wound healing and transwell invasion assays, respectively. Apoptosis and cell cycle arrest were measured by flow cytometry. Moreover, the anticancer mechanism of gossypetin in OSCC cells was analyzed by western blotting. RESULTS: Gossypetin inhibited the proliferation, migration, and invasion of OSCC cells and induced apoptosis by upregulating the Bax/Bcl-2 ratio and cell cycle arrest at the G2/M phase. Furthermore, gossypetin regulated the activation of extracellular signal-regulated kinase and nuclear factor-kappa B. CONCLUSION: Results showed that gossypetin inhibits the proliferation, migration, and invasion of OSCC cells and triggers apoptosis and cell cycle arrest in OSCC. Therefore, gossypetin has the potential for use as a chemopreventive agent in oral cancer.

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Hibiscus , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello , Proliferación Celular , Línea Celular Tumoral , Neoplasias de la Boca/patología , Apoptosis , Movimiento Celular

RESUMEN

INTRODUCTION: Previous research demonstrated benefits of late conversion to mTOR inhibitors against cutaneous squamous cell carcinomas (cSCC) in kidney transplant recipients (KTR), despite of poor tolerability. This study investigated whether stepwise conversion to sirolimus monotherapy without an attack dose modified the course of disease with improved tolerability. METHODS: This prospective exploratory study included non-sensitized KTR with more than 12-months post-transplant, on continuous use of calcineurin inhibitors (CNI)-based therapy, and with poor-prognosis cSCC lesions. Incidence densities of high-risk cSCC over 3-years after conversion to sirolimus-monotherapy were compared to a non-randomized group with high-risk cSCC but unsuitable/not willing for conversion. RESULTS: Forty-four patients were included (83% male, mean age 60 ± 9.7years, 62% with skin type II, mean time after transplantation 9 ± 5.7years). There were 25 patients converted to SRL and 19 individuals kept on CNI. There was a tendency of decreasing density of incidence of all cSCC in the SRL group and increasing in the CNI group (1.49 to 1.00 lesions/patient-year and 1.74 to 2.08 lesions/patient-year, p = 0.141). The density incidence of moderately differentiated decreased significantly in the SRL group while increasing significantly in the CNI group (0.31 to 0.11 lesions/patient-year and 0.25 to 0.62 lesions/patient-year, p = 0.001). In the SRL group, there were no sirolimus discontinuations, no acute rejection episodes, and no de novo DSA formation. Renal function remained stable. CONCLUSIONS: This study suggests that sirolimus monotherapy may be useful as adjuvant therapy of high-risk cSCC in kidney transplant recipients. The conversion strategy used was well tolerated and safe regarding key mid-term transplant outcomes.

Asunto(s)

Carcinoma de Células Escamosas , Trasplante de Riñón , Neoplasias Cutáneas , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Sirolimus/efectos adversos , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Estudios Prospectivos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/inducido químicamente , Inhibidores de la Calcineurina/uso terapéutico , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control

RESUMEN

BACKGROUND: Lichen planus is an inflammatory disease that can affect both the skin and mucous membranes, including the oral mucosa. There is very little original Brazilian dermatology literature about oral lichen planus. OBJECTIVE: To describe the clinical, pathological, and treatment data of 201 patients diagnosed with oral lichen planus followed at the Stomatology Outpatient Clinic of Hospital das Clínicas, Universidade de São Paulo, from 2003 to 2021. METHOD: The patients demographic profile, the morpho-topographic features of the lesions, the treatment employed, and the possible presence of squamous cell carcinoma were analyzed. RESULTS: The disease was more common in women over 50 years of age, tending to be chronic, with a large number of cases showing cicatricial sequelae in the mucosa. Topical treatment with potent corticosteroids was shown to be effective in the vast majority of cases. Squamous cell carcinoma in oral lichen planus cicatricial sequelae was observed in eight cases. STUDY LIMITATIONS: Retrospective study of medical records, with gaps regarding the filling out of data; unequal observation time among the studied cases. CONCLUSIONS: This is the largest Brazilian dermatology series on oral lichen planus. The response to topical corticoid therapy was excellent in the vast majority of cases. The high prevalence of atrophic lesions, demonstrating the chronicity and tissue destruction potential of this disease, may explain the large number of cases of squamous cell carcinoma.

Asunto(s)

Carcinoma de Células Escamosas , Dermatología , Liquen Plano Oral , Liquen Plano , Humanos , Femenino , Persona de Mediana Edad , Liquen Plano Oral/tratamiento farmacológico , Liquen Plano Oral/epidemiología , Liquen Plano Oral/complicaciones , Brasil/epidemiología , Estudios Retrospectivos , Liquen Plano/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología

RESUMEN

BACKGROUND: This study summarized the available evidence about the use of photodynamic therapy (PDT) for the management of oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC). METHODS: An overview of systematic reviews was undertaken based on the 2020 PRISMA statement. Electronic searches were performed in five databases. Studies published up to November 2022 were included. Risk of bias was assessed with the AMSTAR 2 tool. RESULTS: A total of 30 studies enrolling 9,245 individuals with OPMD (n = 7,487) or OSCC (n = 1,758) met the selection criteria. All studies examined the efficacy and/or safety of PDT. OPMD were investigated individually in 82.8% of the studies, the most common being oral lichen planus and actinic cheilitis. OSCC was addressed separately in 10.3% of the studies, while only 6.9% evaluated both OPMD and OSCC. Fourteen different types of photosensitizers were described. PDT was used according to the following setting parameters: 417-670 nm, 10-500 mW/cm2, 1.5-200 J/cm2, and 0.5-143 min. Regarding OPMD, leukoerythroplakia showed the best response rates, while oral lichen planus presented a partial or no response in nearly 75% of documented cases. A complete response was observed in 85.9% of OSCC cases, while 14.1% had no resolution. CONCLUSION: Overall, the response to PDT depended on the type of OPMD/OSCC and the parameters used. Although PDT is an emerging candidate for the treatment of OPMD and OSCC, there is heterogeneity of the methodologies used and the clinical data obtained, particularly regarding the follow-up period.

Asunto(s)

Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Liquen Plano Oral , Enfermedades de la Boca , Neoplasias de la Boca , Fotoquimioterapia , Lesiones Precancerosas , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Liquen Plano Oral/tratamiento farmacológico , Enfermedades de la Boca/tratamiento farmacológico , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Lesiones Precancerosas/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Revisiones Sistemáticas como Asunto

RESUMEN

INTRODUCCIÓN: El carcinoma escamoso es el segundo tumor de piel más frecuente y el responsable de al menos el 20 % de las muertes asociadas al cáncer cutáneo. Junto a las neoplasias malignas de células basales son conocidos colectivamente como cánceres de piel no melanocíticos o carcinomas de queratinocitos. Varios factores de riesgo están asociados con su desarrollo sin embargo el carcinógeno ambiental más reconocido es la luz solar. Afecta principalmente a personas de edad avanzada debido a la acumulación del daño solar o de la exposición a carcinógenos, así como también en poblaciones específicas como los inmunodeprimidos. En estadios tempranos los objetivos principales del tratamiento del cáncer de piel de células escamosas son la extirpación completa del tumor y la preservación máxima de la función y la estética. Generalmente tienen un buen pronóstico, con una sobrevida mayor del 90% a los 5 años. Sin embargo, hasta un 4-6 % de los pacientes presentarán recidivas locorregionales y metástasis a distancia, con sobrevidas a 10 años del 20% en el caso de la enfermedad locorregional avanzada y menor del 10% en el de la enfermedad metastásica. 1­3 En estos pacientes la radioterapia puede indicarse en tumores no resecables o en aquellas personas que no sean operables. El tratamiento sistémico se reserva para los casos que no pueden tratarse con intención curativa ni mediante cirugía y/o radioterapia debido a una extensa diseminación local y/o regional o ante la existencia de metástasis distantes. Dentro de las opciones se encuentran el uso de inhibidores del punto de control inmunitario (ej. pembrolizumab), el uso de quimioterapia sistémica (ej. carboplatino más paclitaxel) o inhibidores del receptor del factor de crecimiento epidérmico (ej. Cetuximab. En este documento se plantea evaluar la eficacia y seguridad del uso de cemiplimab en pacientes con diagnóstico de carcinoma cutáneo de células escamosas avanzado. TECNOLOGÍA: Cemiplimab es un anticuerpo monoclonal humanizado (tipo IgG4) que se une al receptor de muerte celular programada 1 (PD-1) y bloquea su interacción con sus ligandos PD-L1 y PD-L2. El receptor PD-1 es un regulador negativo de la actividad de las células T, involucrado en el control de las respuestas inmunitarias. El bloqueo selectivo de las interacciones de PD-L1/PD-1 y PD-L1/CD80 potencia las respuestas inmunitarias antitumorales e incrementa la activación de las células T. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de cemiplimab en pacientes con diagnóstico de carcinoma cutáneo de células escamosas avanzado. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. EVIDENCIA CLÍNICA: Rischin y col. publicaron en el año 2021 los resultados de un ensayo clínico abierto y no aleatorizado con el objetivo de evaluar la eficacia y la seguridad cemiplimab en adultos con diagnóstico de carcinoma cutáneo de células escamosas metastásico o localmente avanzado que no son candidatos para cirugía o radioterapia (estudio de fase II denominado R2810-ONC1540; NCT02760498). 6 Fueron excluidos aquellos pacientes enfermedad autoinmune que requirió tratamiento sistémico con agentes inmunosupresores en los últimos 5 años; historia de trasplante de órgano sólido; tratamiento previo con anti-PD-1/PD-L1 entre otras situaciones clínicas. El objetivo primario del estudio fue la tasa de respuesta objetiva confirmada (TRO), evaluada mediante una revisión central independiente. Los pacientes fueron enrolados en tres cohortes: pacientes con enfermedad metastásica (cohortes 1 y 3) o localmente avanzada (cohorte 2). Las cohortes 1 y 2 recibieron cemiplimab a una dosis de 3 mg/kg cada dos semanas, mientras que la cohorte 3 lo recibió 350 mg cada tres semanas. CONCLUSIONES: La evidencia que sustenta la aprobación de comercialización de cemiplimab en adultos con carcinoma cutáneo de células escamosas metastásico o localmente avanzado que no son candidatos a tratamiento curativo se basa en un único ensayo clínico no aleatorizado. Este estudio mostraría que en aquellos pacientes que utilizaron cemiplimab las tasas de respuesta serían cercanas al 46,1% y que el 17,% de los participantes experimentaría eventos adversos severos al mediano plazo. La seguridad y eficacia frente a otras opciones disponibles no puede ser establecida debido a que no se encontraron estudios comparativos. Las recomendaciones relevadas lo mencionan como una opción terapéutica más para el tratamiento en pacientes con carcinoma cutáneo de células escamosas metastásico o localmente avanzado que no han recibido previamente otro inhibidor de puntos de control. Su comercialización en la indicación evaluada se encuentra autorizada por las agencias regulatorias de los Estados Unidos y Europa; sin embargo, en Reino Unido y Canadá su cobertura se haya limitada a un acuerdo de comercialización con un descuento en el precio de venta. Utilizando precios de referencia internacionales el costo de adquisición para un ciclo de tratamiento oscilaría de los 5.500 a 10.000 dólares.

Asunto(s)

Humanos , Neoplasias Cutáneas/patología , Inmunoglobulina G/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Argentina , Eficacia , Análisis Costo-Beneficio/economía