RESUMEN
Inhibitor of apoptosis proteins (IAPs) antagonize caspase activation and regulate death receptor signaling cascades. LCL-161 is a small molecule second mitochondrial activator of caspase (SMAC) mimetic, which both disengages IAPs from caspases and induces proteasomal degradation of cIAP-1 and -2, resulting in altered signaling through the NFκB pathway, enhanced TNF production and sensitization to apoptosis mediated by the extrinsic pathway. SMAC mimetics are undergoing clinical evaluation in a range of hematological malignancies. Burkitt-like lymphomas are hallmarked by a low apoptotic threshold, conveying sensitivity to a range of apoptosis-inducing stimuli. While evaluating LCL-161 in the Eµ-Myc model of aggressive Burkitt-like lymphoma, we noted unexpected resistance to apoptosis induction despite 'on-target' IAP degradation and NFκB activation. Moreover, LCL-161 treatment of lymphoma-bearing mice resulted in apparent disease acceleration concurrent to augmented inflammatory cytokine-release in the same animals. Indiscriminate exposure of lymphoma patients to SMAC mimetics may therefore be detrimental due to both unanticipated prolymphoma effects and increased susceptibility to endotoxic shock.
Asunto(s)
Apoptosis/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Linfoma de Células B/patología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/metabolismo , Compuestos de Piridinio/farmacología , Animales , Células Cultivadas , Óxidos N-Cíclicos , Quinasa 9 Dependiente de la Ciclina/metabolismo , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Indolizinas , Linfoma de Células B/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismoRESUMEN
The urinary and renal distribution of Pt following the administration of cis-dichlorodiammine platinum II (cisplatin) to adult male Wistar rats was studied by gel filtration and ion exchange chromatography. Several low molecular weight (LMW) Pt-containing fractions with the same chromatographic properties as those found in urine incubated with cisplatin are present in the kidney cytosol within 15 min of the administration of cisplatin. The concentration of Pt in these fractions decreases rapidly and after 4 h most of the Pt in the kidney cytosol is in a high molecular weight (HMW) fraction which contains 2 subfractions. The smaller fraction (mol. wt. = 20 000), but not the larger (mol. wt greater than 250 000), is also present in the urine of the cisplatin-treated rat, but neither fraction is present in urine incubated with cisplatin and neither is formed by the interaction of cisplatin or the urinary LMW Pt-containing fractions with kidney cytosol in vitro. It is suggested that the smaller fraction may be derived from the filtration and reabsorption of plasma protein-bound Pt, whereas the larger fraction is more likely to be formed exclusively within the kidney cell.