Additive effect of Apo2L/TRAIL and Adeno-p53 in the induction of apoptosisin myeloma cell lines

Objectives. We have previously shown that Adenovirus-p53 (Ad-p53) is a pote nt inducer of apoptosis in myeloma cells expressing nonfunctional p53 and l ow levels of bcl-2 and that Apo2L/TRAIL is a potent inducer of apoptosis, i ndependent of bcl-2. A study was designed to test the synergy between Ad-p5 3 and Apo2L/TRAIL in the induction of apoptosis in relation to the expressi on of DR4/DR5 and DcR1, in cells undergoing Ad-p53-induced apoptosis. Methods. Replication deficient Ad-p53 and human recombinant Apo2L/TRAIL wer e used. Myeloma cells with mutated/w.t. p53 and varying expression of bcl-2 were used to test the effect of Ad-p53, Apo2L/TRAIL, or both, on apoptosis , measured by annexin V. Results. Treatment with Ad-p53 resulted in a dose-dependent apoptosis conco mitant with a dose-dependent increase in the expression of DR4/DR5 and a de crease in the expression of DcR1, in Ad-p53-sensitive cell lines. In these cells, addition of Apo2L/TRAIL to cells treated with Ad-p53 resulted in a d ose-dependent increase in apoptosis. Myeloma cells resistant to Ad-p53 had high levels of DR4/DR5 and high levels of DcR1 and treatment with Ad-p53 di d not reduce the expression of DcR1. Also, addition of Apo2L/TRAIL to Ad-p5 3 did not affect the level of apoptosis beyond the level of apoptosis obser ved with Apo2L/TRAIL alone. Conclusions. 1) Cotreatment with Ad-p53 and Apo2L/TRAIL resulted in additiv e apoptosis in myeloma cells expressing nonfunctional p53 and low levels of bcl-2. 2) Resistance to Ad-p53 or to the combination of Ad-p53 and Apo2L/T RAIL was not due to the lack of adenovirus receptor (CAR) or low expression of DR4/DR5 but rather due to the relatively high expression of DcR1 recept or. (C) 2001 International Society for Experimental Hematology. Published b y Elsevier Science Inc.