Ionizing radiation sensitizes erythroleukemic cells but not normal erythroblasts to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity by selective up-regulation of TRAIL-R1

Cytotoxic activity of tumor necrosis factor-related apoptosis-inducing liga nd (TRAIL/Apo-2 ligand), used alone or in different combinations with eithe r a low (1.5 Gy) or a high (15 Gy) single dose of ionizing radiation (IR), was investigated on erythroleukemic cells (K562, HEL, Friend, primary leuke mic erythroblasts) and on primary CD34(+)-derived normal erythroblasts, Hum an recombinant TRAIL alone variably affected the survival/growth of erythro leukemic cells; K562 cells were the most sensitive. Moreover, all erythrole ukemic cells were radio-resistant, as demonstrated by the fact that cytotox icity was evident only after treatment with high-dose (15 Gy) IR. Remarkabl y, when IR and TRAIL were used in combination, an additive effect was notic ed in all erythroleukemic cells. Augmentation of TRAIL-induced cell death b y IR was observed with both low and high IR doses and required the sequenti al treatment of IR 3 to 6 hours before the addition of TRAIL. Conversely, b oth TRAIL and IR showed a moderate cytotoxicity on primary CD34(+)-derived normal erythroblasts when used atone, but their combination did not show an y additive effect. Moreover, the cytotoxicity of IR plus TRAIL observed in erythroleukemic cells was accompanied by the selective up-regulation of the surface expression of TRAIL-R1 (DR4), and it was completely blocked by the z-Val-Ala-Asp (OMe)-CH2 (r-VAD-fmk) caspase inhibitor. On the other hand, the surface expression of TRAIL-R1 in CD34(+)-derived normal erythroblasts was unaffected by IR, which induced the up-regulation of the decoy TRAIL-R3 . These data demonstrate that treatment with IR provides an approach to sel ectively sensitize erythroleukemic cells, but not normal erythroblasts, to TRAIL-induced apoptosis through the functional up-regulation of TRAIL-R1. ( Blood.2001;97:2596-2603) (C) 2001 by The American Society of Hematology.