RESUMO
The success of chemotherapy regimens in patients with non-small cell lung cancer (NSCLC) could be restricted at least in part by cancer stem cells (CSC) niches within the tumor microenvironment (TME). CSC express CD133, CD44, CD47, and SOX2, among other markers and factors. Analysis of public data revealed that high expression of hyaluronan (HA), the main glycosaminoglycan of TME, correlated positively with CSC phenotype and decreased disease-free interval in NSCLC patients. We aimed to cross-validate these findings on human and murine lung cancer cells and observed that CD133 + CSC differentially expressed higher levels of HA, HAS3, ABCC5, SOX2, and CD47 (p < 0.01). We modulated HA expression with 4-methylumbelliferone (4Mu) and detected an increase in sensitivity to paclitaxel (Pa). We evaluated the effect of 4Mu + chemotherapy on survival, HA metabolism, and CSC profile. The combination of 4Mu with Pa reduced the clonogenic and tumor-forming ability of CSC. Pa-induced HAS3, ABCC5, SOX2, and CD47 expression was mitigated by 4Mu. Pa + 4Mu combination significantly reduced in vivo tumor growth, enhancing animal survival and restoring the CSC profile in the TME to basal levels. Our results suggest that HA is involved in lung CSC phenotype and chemosensitivity, and its modulation by 4Mu improves treatment efficacy to inhibit tumor progression.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Ácido Hialurônico , Himecromona , Neoplasias Pulmonares , Células-Tronco Neoplásicas , Paclitaxel , Microambiente Tumoral , Ácido Hialurônico/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Animais , Camundongos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Himecromona/farmacologia , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologiaRESUMO
BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. EXPERIMENTAL APPROACH: Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. KEY RESULTS: Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. CONCLUSION AND IMPLICATIONS: TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.
Assuntos
Paclitaxel , Doenças do Sistema Nervoso Periférico , Humanos , Camundongos , Animais , Paclitaxel/toxicidade , PPAR gama , Fator Neurotrófico Derivado do Encéfalo , Fator 2 Relacionado a NF-E2 , Doenças Neuroinflamatórias , Qualidade de Vida , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controleRESUMO
Docetaxel (DTX) is one of the chemotherapeutic drugs indicated as a first-line treatment against metastatic prostate cancer (mPCa). This study aimed to compare the impact of DTX on mPCa (DU-145) tumor cells cultured as 2D monolayers and 3D multicellular tumor spheroids (MCTS) in vitro. The cells were treated with DTX (1-96 µM) at 24, 48, or 72 hr in cell viability assays (resazurin, phosphatase acid, and lactate dehydrogenase). Cell death was assessed with fluorescent markers and proliferation by clonogenic assay (2D) and morphology, volume, and integrity assay (3D). The cell invasion was determined using transwell (2D) and extracellular matrix (ECM) (3D). Results showed that DTX decreased cell viability in both culture models. In 2D, the IC50 (72 hr) values were 11.06 µM and 14.23 µM for resazurin and phosphatase assays, respectively. In MCTS, the IC50 values for the same assays were 114.9 µM and 163.7 µM, approximately 10-fold higher than in the 2D model. The % of viable cells decreased, while the apoptotic cell number was elevated compared to the control in 2D. In 3D spheroids, only DTX 24 µM induced apoptosis. DTX (≥24 µM at 216 hr) lowered the volume, and DTX 96 µM completely disintegrated the MCTS. DTX reduced the invasion of mPCa cells to matrigel (2D) and migration from MCTS to the ECM. Data demonstrated significant differences in drug response between 2D and 3D cell culture models using mPCa DU-145 tumor cells. MCTS resembles the early stages of solid tumors in vivo and needs to be considered in conjunction with 2D cultures when searching for new therapeutic targets.
Assuntos
Antineoplásicos , Neoplasias da Próstata , Masculino , Humanos , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Próstata , Linhagem Celular Tumoral , Esferoides Celulares , Neoplasias da Próstata/tratamento farmacológico , Monoéster Fosfórico Hidrolases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Chemotherapy-induced neuropathic pain (CINP) is one of the most severe side effects of anticancer agents, such as platinum- and taxanes-derived drugs (oxaliplatin, cisplatin, carboplatin and paclitaxel). CINP may even be a factor of interruption of treatment and consequently increasing the risk of death. Besides that, it is important to take into consideration that the incidence of cancer is increasing worldwide, including colorectal, gastric, lung, cervical, ovary and breast cancers, all treated with the aforementioned drugs, justifying the concern of the medical community about the patient's quality of life. Several physiopathological mechanisms have already been described for CINP, such as changes in axonal transport, mitochondrial damage, increased ion channel activity and inflammation in the central nervous system (CNS). Another less frequent event that may occur after chemotherapy, particularly under oxaliplatin treatment, is the central neurotoxicity leading to disorders such as mental confusion, catatonia, hyporeflexia, etc. To date, no pharmacological therapy has shown satisfactory effect in these cases. In this scenario, duloxetine is the only drug currently in clinical use. Peroxisome proliferator-activated receptors (PPARs) belong to the class of nuclear receptors and are present in several tissues, mainly participating in lipid and glucose metabolism and inflammatory response. There are three PPAR isoforms: α, ß/δ and γ. PPARγ, the protagonist of this review, is expressed in adipose tissue, large intestine, spleen and neutrophils. This subtype also plays important role in energy balance, lipid biosynthesis and adipogenesis. The effects of PPARγ agonists, known for their positive activity on type II diabetes mellitus, have been explored and present promising effects in the control of neuropathic pain, including CINP, and also cancer. This review focuses largely on the mechanisms involved in chemotherapy-induced neuropathy and the effects of the activation of PPARγ to treat CINP. It is the aim of this review to help understanding and developing novel CINP therapeutic strategies integrating PPARγ signalling.
RESUMO
Introdução: A avaliação da resposta à quimioterapia de indução (QI) com regimes triplos, incluindo taxane, cisplatina e 5 fluorouracil (TPF) em carcinoma de células escamosas de cabeça e pescoço localmente avançado (CECCPLA) é geralmente realizada após 2 ciclos de quimioterapia usando critérios morfológicos. Preocupações em relação ao perfil de toxicidade do TPF sugerem um benefício potencial de uma abordagem de avaliação de resposta precoce. Objetivo: o objetivo deste estudo é avaliar a utilidade de se avaliar precocemente a resposta tumoral por método funcional e morfológico com uso do PET-SCAN em pacientes portadores de CECCPLA tratados com QI seguido de radioteapia após o primeiro ciclo de QI. Métodos: Pacientes com CECCPLA que se submeteram ao QI com TPF foram avaliados prospectivamente. Os procedimentos de estadiamento incluíram imagem locorregional e de tórax, exame endoscópico e PET-SCAN. Pacientes foram avaliados para resposta tumoral após o segundo ciclo da QI e ao término do tratamento, conforme conduta estabelecida para a prática clínica. No dia 14 do primeiro ciclo, um segundo PET- SCAN foi realizado e os médicos e pacientes foram cegados para os seus resultados. Todos os pacientes assinaram consentimento para participação do estudo. Resultados: Entre fevereiro de 2010 e julho de 2013, 49 pacientes portadores de CECCPLA estádio III / IVA-B CECCPLA foram recrutados. Após um seguimento mediano de 44,3 meses, pacientes cujos achados de PET-SCAN não registraram aumento no Stardard Uptake Value (SUV) máximo dos linfonodos regionais apresentaram melhor sobrevida livre de recidiva (HR = 0,18; IC95% 0,056-0,585; p = 0,004) e sobrevida global (HR = 0,14, IC 95% 0,040-0,498; p = 0,002) e foram considerados respondedores. Neste subgrupo, os pacientes que atingiram pelo menos 45% de redução no SUV máximo do tumor primário apresentaram melhor sobrevida livre de progressão tumoral (HR = 0,23, IC 95% 0,062-0,854; p = 0,028) e sobrevida global (HR = 0,11, IC 95% 0,013 -0,96; p = 0,046). Conclusão: Estes resultados sugerem um potencial papel da avaliação da resposta tumoral precoce com PET-SCAN em pacientes com CECCPLA submetidos a QI. Aumento no SUV máximo do linfonodo regional e diminuição insuficiente na captação do tumor primário predizem pior evolução clínica (AU)
Introduction: Evaluation of induction chemotherapy (IC) response with triplet taxane, cisplatin and 5 fluorouracil containing regimen (TPF) in locally advanced head and neck squamous cell carcinoma (LASCCHN) is usually performed after 2 cycles of chemotherapy using morphological criteria. Concerns regarding the TPF toxicity profile suggest a potential benefit of an early tumor response assessment approach. Objective: The objective of this study is to evaluate the usefulness of early evaluation of tumor response by functional and morphological method using PET-SCAN patients with LASCCHN treated with IC followed by radiotherapy after the first IC cycle. Methods: Patients with LASCCHN who underwent IC with TPF were prospectively evaluated. Staging procedures included standard primary neck tumor and chest imaging, endoscopic examination and PET-SCAN. Patients were evaluated for tumor response after the second cycle of IC and at the end of treatment, according to established practice guidelines. On day 14 of the first cycle, a second PET-SCAN was performed and physicians and patients were blinded to their exam findings. Results: Between February 2010 and July 2013, 49 patients staged AJCC III / IVA-B LASCCHN were recruited. After a median follow-up of 44.3 months, patients with no increase in the regional maximum lymph node SUV had better relapse-free survival (HR = 0.18, 95% CI 0.056-0.585, p = 0.004) and overall survival (HR = 0.14, 95% CI 0.040-0.498, p = 0.002) and were considered responders. Among cases considered responders, patients who achieved at least 45% reduction of SUV in the primary tumor presented improvement in progression-free (HR = 0.23, 95% CI 0.062-0.854, p = 0.028) and overall survival (HR = 0.11, 95% CI 0.013 -0.96, p = 0.046). All patients provided informed consent for study participation. Conclusion: These results suggest an important role of the evaluation of the early response with PET-SCAN in patients with LASCCHN undergoing IC. Increase in the regional SUV maximum and insufficient decrease in primary tumor uptake predict worse clinical outcome (AU)
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Papillomaviridae , Radioterapia , Carcinoma de Células Escamosas , Quimioterapia de Indução , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias de Cabeça e PescoçoRESUMO
Los avances recientes en el tratamiento de las enfermedades neoplásicas han mejorado las tasas de supervivencia. Las intervenciones médicas generan diversos efectos adversos agudos que comprometen el tracto gastrointestinal y la medula ósea, mientras la neurotoxicidad tiende a ser tardía y evoluciona en el tiempo. En el sistema nervioso periférico es frecuente documentar la neuropatía inducida por el tratamiento médico del cáncer, hallazgo relacionado con la administración de agentes quimioterapéuticos utilizados para controlar los tumores hematológicos y sólidos. El tratamiento oncológico genera una gran variedad de cambios estructurales y funcionales en los nervios periféricos, incluyendo la afectación de los cuerpos neuronales del sistema de transporte axonal, del recubrimiento mielínico y de las estructuras de soporte glial. Cada agente presenta un espectro de toxicidad único que se relaciona con su mecanismo de acción, eventos que pueden mitigarse gracias a los resultados de múltiples estudios. Gracias al reconocimiento de los efectos devastadores de la neuropatía inducida por el tratamiento médico del cáncer en la calidad de vida, la investigación básica y clínica ha empezado a evaluar el papel de múltiples terapias para prevenir y tratar el daño neurológico. Esta revisión integra información seleccionada a partir de búsquedas estructuras realizadas en las bases de datos biomédicas más relevantes, haciendo énfasis en el diagnóstico y en las intervenciones farmacológicas y no farmacológicas descritas como parte del manejo de la neuropatía inducida por el tratamiento médico del cáncer, que con frecuencia es subvalorada. En conclusión, la información disponible hasta el momento permite establecer los mecanismos de la enfermedad y sugiere el desarrollo de un número mayor de estudios que permitan validar las estrategias descritas hasta el momento.
Recent advances in the development and administration of therapy for malignant diseases have been rewarded with prolonged survival rates. Unlike more immediate toxicities that affect the gastrointestinal tract and bone marrow, chemotherapy-induced neurotoxicity is frequently delayed in onset and may progress over time. In the peripheral nervous system, the major brunt of the toxicity is directed against the peripheral nerve, resulting in cancer therapy-induced peripheral neuropathy. Chemotherapeutic agents used to treat hematologic and solid tumors target a variety of structures and functions in the peripheral nervous system, including the neuronal cell body, the axonal transport system, the myelin sheath, and glial support structures. Each agent exhibits a spectrum of effects unique to its mechanism of action, and recent studies in this fi eld have yielded clearer ideas on how to mitigate injury. Combined with the call for a greater recognition of the devastating effects of cancer therapy-induced peripheral neuropathy on quality of life, basic and clinical researchers have begun to investigate therapy to prevent and treat neurologic damage. This review was made based on relevant information avaliable on international databases concerning cancer therapyinduced peripheral neuropathy and summarizes the evidence for diagnosis, pharmacologic and nonpharmacologic approaches to the management of this commonly unrecognized condition. In conclusion, the information avaliable in this moment establish the mechanisms of the disease and exposes the importance of the development of statistically stronger clinical trials that complement current data available in this moment.