Glucosamine induces cell death via proteasome inhibition in human ALVA41 prostate cancer cell

Glucosamine, a naturally occurring amino monosaccharide, has been reported to play a role in the regulation of apoptosis more than half century. However the effect of glucosamine on tumor cells and the involved molecular mechanisms have not been thoroughly investigated. Glucosamine enters the hexosamine biosynthetic pathway (HBP) downstream of the rate-limiting step catalyzed by the GFAT (glutamine:fluctose-6-phosphate amidotransferase), providing UDP-GlcNAc substrates for O-linked beta-N-acetylglucosamine (O-GlcNAc) protein modification. Considering that O-GlcNAc modification of proteasome subunits inhibits its activity, we examined whether glucosamine induces growth inhibition via affecting proteasomal activity. In the present study, we found glucosamine inhibited proteasomal activity and the proliferation of ALVA41 prostate cancer cells. The inhibition of proteasomal activity results in the accumulation of ubiquitinated proteins, followed by induction of apoptosis. In addition, we demonstrated that glucosamine downregulated proteasome activator PA28gamma and overexpression of PA28gamma rescued the proteasomal activity and growth inhibition mediated by glucosamine. We further demonstrated that inhibition of O-GlcNAc abrogated PA28gamma suppression induced by glucosamine. These findings suggest that glucosamine may inhibit growth of ALVA41 cancer cells through downregulation of PA28gamma and inhibition of proteasomal activity via O-GlcNAc modification.

Bortezomib como alternativa en el tratamiento de pacientes con gammapatías malignas / Bortezomib as an alternative in the treatment of patients with malignant gammopathy

Objetivo: Describir el uso de bortezomib en un hospital comarcal como alternativa en el tratamiento de gammapatías malignas. Métodos: Análisis retrospectivo de los pacientes tratados con bortezomib en nuestro hospital desde noviembre de 2005 hasta octubre de 2007. A partir de la revisión de las historias clínicas de los pacientes se recogieron los datos correspondientes al diagnóstico, tratamientos previos a bortezomib, fecha de la última progresión de la enfermedad, número de ciclos de bortezomib, respuesta a éste, super vivencia global y libre de progresión, complicaciones y efectos secundarios. Resultados: El 47% de los pacientes estudiados eran varones (5/12), con una mediana de edad de 67 años (rango, 40-81 años). El diagnóstico principal fue mieloma múltiple, solo o asociado a plasmocitoma. El inicio con bortezomib coincidió con la última progresión de la enfermedad en el 83% de los pacientes (10/12). El 50% completó 7-8 ciclos con bortezomib. Se obtuvo respuesta en el 58% de los pacientes (7/12), alcanzándose criterios de respuesta parcial en el 33% (4/12) y respuesta completa en el 25% (3/12). Las reacciones adversas más frecuentes fueron neuropatía y toxicidad gastrointestinal, y supuso la suspensión del tratamiento en el 50% de los casos. Conclusiones: Según los resultados obtenidos, bortezomib es una buena alternativa en el tratamiento de las gammapatías malignas, sobre todo en el caso de plasmocitomas (AU)

Objective: To describe the use of bortezomib in a district hospital as an alternative in the treatment of malignant gammopathy. Methods: A retrospective analysis was carried out on patients treated with bortezomib in our hospital between November 2005 and October 2007. The patients’ medical histories were used to obtain data regarding diagnosis, treatments prior to bortezomib, date of the last disease progression, number of bortezomib courses, response to bortezomib, overall and event free survival. Results: 47% of the patients studied were male (5/12). The medianage was 67, (age range between 40 and 81). The main diagnosis was multiple myeloma on its own or associated with plasmocytoma. Bortezomib initiation coincided with the last disease progression in 83%of patients (10/12). 50% of the patients completed 7-8 courses of bortezomib. Response was seen in 58% of the patients (7/12), partial response in 33% of them (4/12) and complete response in 25%(3/12). The most common adverse reactions were neuropathy and gastrointestinal toxicity which required treatment to be discontinued in 50% of cases. Conclusions: According to the results obtained, bortezomib is a good alternative in the treatment of malignant gammopathy, above all in the case of plasmocytomas (AU)