RESUMO
BACKGROUND AND PURPOSE: Follicular lymphoma is the second most common non-Hodgkin's lymphoma and, despite the introduction of rituximab for its treatment, this disease is still considered incurable. Besides genetic alterations involving Bcl-2, Bcl-6 or c-Myc, follicular lymphoma cells often display altered B-cell receptor signalling pathways including overactive PKC and PI3K/Akt systems. EXPERIMENTAL APPROACH: The effect of enzastaurin, an inhibitor of PKC, was evaluated both in vitro on follicular lymphoma cell lines and in vivo on a xenograft murine model. Using pharmacological inhibitors and siRNA transfection, we determined the different signalling pathways after enzastaurin treatment. KEY RESULTS: Enzastaurin inhibited the serine-threonine kinase p90RSK which has downstream effects on GSK3ß. Bad and p70S6K. These signalling proteins control follicular lymphoma cell survival and apoptosis; which accounted for the inhibition by enzastaurin of cell survival and its induction of apoptosis of follicular lymphoma cell lines in vitro. Importantly, these results were replicated in vivo where enzastaurin inhibited the growth of follicular lymphoma xenografts in mice. CONCLUSIONS AND IMPLICATIONS: The targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.
Assuntos
Antineoplásicos/farmacologia , Linfoma Folicular/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Linfoma Folicular/enzimologia , Linfoma Folicular/genética , Camundongos , Camundongos SCID , Terapia de Alvo Molecular , Fosforilação , Interferência de RNA , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
The clinical and pathological features of 14 cases of Merkel cell carcinoma are reported. They commonly arise in the skin of elderly patients, particularly on the face and pelvis. They have a loco-regional aggressivity (nodal metastases in 4 cases) but some patients die with disseminated metastases (2 cases). These tumors are composed of round cells with scanty cytoplasm, arranged in solid or trabecular sheets. Mitotic figures are usually numerous. The ultrastructural study reveal secretory granules and paranuclear collection of intermediate filaments. Immunohistochemical phenotype is highly characteristic: cytoplasmic diffuse positivity with an anti-neuron-specific enolase polyclonal antibody; polar and/or diffuse positivity with anti-cytokeratin, anti-epithelial membrane antigen and anti-S100 protein monoclonal antibodies; polar positivity with an anti-neurofilament monoclonal antibody. The negativity with an anti-common leucocyte antigen monoclonal antibody is helpful to differentiate Merkel cell carcinoma from cutaneous malignant lymphoma.
