RESUMEN
JAK proteins have been linked with survival and proliferation of multiple myeloma (MM) cells; therefore, JAK inhibition could be a therapeutic strategy for MM. We evaluated JAK1 and JAK2 expression in MM patients and the effects of JAK/STAT pathway inhibition on apoptosis, cell cycle, gene and protein expression in RPMI-8226 and U266 MM cell lines. 57% of patients presented overexpression of JAK2 and 27%, of JAK1. After treatment with ruxolitinib and bortezomib, RPMI-8226 and U266 presented 50% of cells in late apoptosis, reduction of anti-apoptotic genes expression and higher number of cells in SubG0 phase. Co-culture with stromal cells protected RPMI-8226 cells from apoptosis, which was reversed by lenalidomide addition. Combination of ruxolitinib, bortezomib and lenalidomide induced 72% of cell death, equivalent to bortezomib, lenalidomide and dexamethasone, combination used in clinical practice. Many JAK/STAT pathway genes, after treatment, had their expression reduced, mainly in RPMI-8226, with insignificant changes in U266. In this scenario, JAK/STAT pathway could pose as a new therapeutic target to be exploited, since it is constitutively active and contributes to survival of MM tumor cells.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bortezomib/farmacología , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Mieloma Múltiple/tratamiento farmacológico , Pirazoles/farmacología , Factores de Transcripción STAT/metabolismo , Transducción de Señal/efectos de los fármacos , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Técnicas de Cocultivo , Relación Dosis-Respuesta a Droga , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Janus Quinasa 1/genética , Janus Quinasa 1/metabolismo , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/enzimología , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Nitrilos , Pirimidinas , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Células del Estroma/patología , Talidomida/farmacología , Factores de TiempoRESUMEN
The aim of the present study was to determine whether there is an association between serum free light chains (sFLC) quantification and the development of post-transplant lymphoproliferative disorder (PTLD), using serum samples from a nested case-control cohort of patients with renal transplant. Ten new cases of PTLD and 46 controls were enrolled. Additional comparison groups consisted of five human immunodeficiency virus (HIV)-infected individuals, five with untreated Hodgkin lymphoma and six normal individuals. Serum κ and λ FLC concentrations were measured by nephelometry and compared with reference ranges (normal and renal ranges). κ and/or λ were above the normal range in 90% of cases and in 65% of matched controls. There was no statistically significant difference between all groups, except for λ FLC concentrations between cases of PTLD and normal individuals (p = 0.016). The κ/λ sFLC ratios of cases and controls were within the renal range and normal range. Our results suggest that sFLC are not useful to predict PTLD development in renal transplant recipients.
