RESUMO
he bisphosphonates are synthetic substances of inorganic pyrophosphate that havebeen the basis of treatment of patients with osteolytic diseases, such as multiple myeloma, malignanthypercalcemia, Paget's disease, or patients with bone metastases. Its main pharmacological effect is inhibitionof bone resorption caused by osteoclasts, which have a reduced function. Their adverse effects are infrequentbut include pyrexia, impaired renal function, hypocalcemia, and more recently, maxillo-mandibular ostenecroseinduced bofosfonatos. In this report we describe a clinical case of jaw osteonecrosis induced by bisphosphonatesin patient with chronic kidney disease and the treatment protocol performed
Los bisfosfonatos son sustancias sintéticas de pirofosfato inorgánico que han sido la base del tratamiento de pacientes con enfermedades osteolíticas, como mieloma múltiple, hipercalcemia maligna, enfermedad de Paget o pacientes con metástasis ósea. Su principal efecto farmacológico es la inhibición dela resorción ósea causada por osteoclastos, que tienen una función reducida. Sus efectos adversos son infrecuentes, pero incluyen pirexia, deterioro de la función renal, hipocalcemia y, más recientemente, indujo inducido por bicosfonatos maxilomandibular. En este informe se describe un caso clínico de osteonecrosis mandibular inducida por bifosfonatos en pacientes con enfermedad renal crónica y el protocolo de trata-miento realizado.
Assuntos
Humanos , Masculino , Idoso , Insuficiência Renal Crônica/terapia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Radiografia PanorâmicaRESUMO
Fatty acid synthase (FASN) is responsible for the endogenous production of fatty acids from acetyl-CoA and malonyl-CoA. Its overexpression is associated with poor prognosis in human cancers including melanomas. Our group has previously shown that the inhibition of FASN with orlistat reduces spontaneous lymphatic metastasis in experimental B16-F10 melanomas, which is a consequence, at least in part, of the reduction of proliferation and induction of apoptosis. Here, we sought to investigate the effects of pharmacological FASN inhibition on lymphatic vessels by using cell culture and mouse models. The effects of FASN inhibitors cerulenin and orlistat on the proliferation, apoptosis, and migration of human lymphatic endothelial cells (HDLEC) were evaluated with in vitro models. The lymphatic outgrowth was evaluated by using a murine ex vivo assay. B16-F10 melanomas and surgical wounds were produced in the ears of C57Bl/6 and Balb-C mice, respectively, and their peripheral lymphatic vessels evaluated by fluorescent microlymphangiography. The secretion of vascular endothelial growth factor C and D (VEGF-C and -D) by melanoma cells was evaluated by ELISA and conditioned media used to study in vitro lymphangiogenesis. Here, we show that cerulenin and orlistat decrease the viability, proliferation, and migration of HDLEC cells. The volume of lymph node metastases from B16-F10 experimental melanomas was reduced by 39% in orlistat-treated animals as well as the expression of VEGF-C in these tissues. In addition, lymphatic vessels from orlistat-treated mice drained more efficiently the injected FITC-dextran. Orlistat and cerulenin reduced VEGF-C secretion and, increase production of VEGF-D by B16-F10 and SK-Mel-25 melanoma cells. Finally, reduced lymphatic cell extensions, were observed following the treatment with conditioned medium from cerulenin- and orlistat-treated B16-F10 cells. Altogether, our results show that FASN inhibitors have anti-metastatic effects by acting on lymphatic endothelium and melanoma cells regardless the increase of lymphatic permeability promoted by orlistat.
Assuntos
Cerulenina/farmacologia , Ácido Graxo Sintases/antagonistas & inibidores , Lactonas/farmacologia , Vasos Linfáticos/efeitos dos fármacos , Melanoma Experimental/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Inibidores da Síntese de Ácidos Graxos/farmacologia , Humanos , Linfangiogênese/efeitos dos fármacos , Metástase Linfática , Vasos Linfáticos/metabolismo , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Orlistate , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator D de Crescimento do Endotélio Vascular/metabolismoRESUMO
Fatty acid synthase (FASN) is the biosynthetic enzyme responsible for the endogenous synthesis of fatty acids. It is downregulated in most normal cells, except in lipogenic tissues such as liver, lactating breast, fetal lung, and adipose tissue. Conversely, several human cancers, including head and neck squamous cell carcinomas (HNSCC), overexpress FASN, which has been associated with poor prognosis and recently suggested as a metabolic oncoprotein. Orlistat is an irreversible inhibitor of FASN activity with cytotoxic properties on several cancer cell lines that inhibits tumor progression and metastasis in prostate cancer xenografts and experimental melanomas, respectively. To explore whether the inhibition of FASN could impact oral tongue squamous cell carcinoma (OTSCC) metastatic spread, an orthotopic model was developed by the implantation of SCC-9 ZsGreen LN-1 cells into the tongue of BALB/c nude mice. These cells were isolated through in vivo selection, show a more invasive behavior in vitro than the parental cells, and generate orthotopic tumors that spontaneously metastasize to cervical lymph nodes in 10 to 15 days only. SCC-9 ZsGreen LN-1 cells also exhibit enhanced production of MMP-2, ERBB2, and CDH2. The treatment with orlistat reduced proliferation and migration, promoted apoptosis, and stimulated the secretion of VEGFA165b by SCC-9 ZsGreen LN-1 cells. In vivo, the drug was able to decrease both the volume and proliferation indexes of the tongue orthotopic tumors and, importantly, reduced the number of metastatic cervical lymph nodes by 43%. These results suggest that FASN is a potential molecular target for the chemotherapy of patients with OTSCC.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Ácido Graxo Sintase Tipo I/genética , Neoplasias da Língua/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Humanos , Lactonas/administração & dosagem , Camundongos , Metástase Neoplásica , Orlistate , Neoplasias da Língua/genética , Neoplasias da Língua/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Fatty acid synthase (FASN) is the enzyme responsible for the endogenous synthesis of the saturated fatty acid palmitate. In contrast to most normal cells, malignant cells depend on FASN activity for growth and survival. In fact, FASN is overexpressed in a variety of human cancers including cutaneous melanoma, in which its levels of expression are associated with a poor prognosis and depth of invasion. Here, we show that the specific inhibition of FASN activity by the antiobesity drug Orlistat or siRNA is able to significantly reduce proliferation and promote apoptosis in the mouse metastatic melanoma cell line B16-F10. These results prompted us to verify the effect of FASN inhibition on the metastatic process in a model of spontaneous melanoma metastasis, in which B16-F10 cells injected in the peritoneal cavity of C57BL/6 mice metastasize to the mediastinal lymph nodes. We observed that mice treated with Orlistat 48 hr after the inoculation of B16-F10 cells exhibited a 52% reduction in the number of mediastinal lymph node metastases, in comparison with the control animals. These results suggest that FASN activity is essential for B16-F10 melanoma cell proliferation and survival while its inactivation by Orlistat significantly reduces their metastatic spread. The chemical inhibition of FASN activity could have a potential benefit in association with the current chemotherapy for melanoma.