Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells

In present studies, treatment with tumor necrosis factor (TNF)-related apop tosis inducing ligand (TRAIL, also known as Apo-beta ligand [Apb-2L]) is sh own to induce apoptosis of the human acute leukemia HL-60, U937, and Jurkat cells in a dose-dependent manner, with the maximum effect seen following t reatment of Jurkat cells with 0.25 mug/mL of Apo-2L (95.0% +/- 3.5% of apop totic cells). Susceptibility of these acute leukemia cell types, which are known to lack p53(wt) function, did not appear to correlate with the levels of the apoptosis-signaling death receptors (DRs) of Apo-2L, ie, DR4 and DR 5; decoy receptors (DcR1 and 2); FLAME-1 (cFLIP); or proteins in the inhibi tors of apoptosis proteins (IAP) family. Apo-2L-induced apoptosis was assoc iated with the processing of caspase-8, Bid, and the cytosolic accumulation of cytochrome c as well as the processing of caspase-9 and caspase-3. Apo- 2L-induced apoptosis was significantly inhibited in HL-60 cells that overex pressed Bcl-2 or Bcl-x(L). Cotreatment with either a caspase-8 or a caspase -9 inhibitor suppressed Apo-2L-induced apoptosis. Treatment of human leukem ic cells with etoposide, Ara-C, or doxorubicin increased DR5 but not DR4, F as, DcR1, DcR2, Fas ligand, or Apo-2L levels. importantly sequential treatm ent of HL-60 cells with etoposide, Ara-C, or doxorubicin followed by Apo-2L induced significantly more apoptosis than treatment with Apo-2L, etoposide , doxorubicin, or Ara-C alone, or cotreatment with Apo-2L and the antileuke mic drugs, or treatment with the reverse sequence of Apo-2L followed by one of the antileukemic drugs. These findings indicate that treatment with eto poside, Ara-C, or doxorubicin up-regulates DR5 levels in a p53-independent manner and sensitizes human acute leukemia cells to Ape-at-induced apoptosi s. (C) 2000 by The American Society of Hematology.