RESUMEN
Galectins constitute a family of lectins that specifically exhibit the affinity for beta-galactosides and modulate various biological events. Galectin-9 is a tandem-repeat type galectin with two carbohydrate recognition domains and has recently been shown to have an anti-proliferative effect on cancer cells. We investigated the effect of recombinant protease-resistant galectin-9 (hGal9) on multiple myeloma (MM). In vitro, hGal9 inhibited the cell proliferation of five myeloma cell lines examined, including a bortezomib-resistant subcell line, with IC(50) between 75.1 and 280.0 nM, and this effect was mediated by the induction of apoptosis with the activation of caspase-8, -9, and -3. hGal9-activated Jun NH(2)-terminal kinase (JNK) and p38 MAPK signaling pathways followed by H2AX phosphorylation. Importantly, the inhibition of either JNK or p38 MAPK partly inhibited the anti-proliferative effect of hGal9, indicating the crucial role of these pathways in the anti-MM effect of hGal9. hGal9 also induced cell death in patient-derived myeloma cells, some with poor-risk factors, such as chromosomal deletion of 13q or translocation t(4;14)(p16;q32). Finally, hGal9 potently inhibited the growth of human myeloma cells xenografted in nude mice. These suggest that hGal9 is a new therapeutic target for MM that may overcome resistance to conventional chemotherapy.
Asunto(s)
Galectinas/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Ácidos Borónicos/farmacología , Bortezomib , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Perfilación de la Expresión Génica , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Quinasas Quinasa Quinasa PAM/genética , Ratones , Ratones Desnudos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Mutación/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosforilación , Proteínas Proto-Oncogénicas/genética , Pirazinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Irradiación Corporal Total , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Although eosinophilia is one of the typical clinical features of some helminth infections, the degree of eosinophilia in helminthiasis is usually 10% to 30% with a total white blood cell count of 10,000 to 20,000/mm3. Here we report a case of extraordinarily high eosinophilia (91%; absolute eosinophil count, 84,000/mm3) caused by Paragonimus westermani infection. To determine the mechanisms of eosinophilia, the levels of several eosinophilopoietic cytokines in the patient's sera were measured during the course of treatment. METHODS: Serum levels of three cytokines, granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 were measured by enzyme-linked immunosorbent assay using commercial kits or our own assay system for IL-5. RESULTS: Although the kinetic changes of IL-5 correlated well with eosinophilia, the serum IL-3 level remained below the detection level throughout the period examined. Although the granulocyte-macrophage colony-stimulating factor level was twofold to threefold higher than the normal level, its kinetics did not parallel the degree of eosinophilia. CONCLUSIONS: These results show that Paragonimus westermani infection can induce an extraordinarily high level of eosinophilia with an associated increase in IL-5 production. Immunoserologic diagnosis for parasitic diseases should be included in the differential diagnosis of eosinophilia.
