Cell surface-directed interaction of anthracyclines leads to cytotoxicity and nuclear factor kappa B activation but not apoptosis signaling

Anthracyclines are, above all, DNA intercalators, which induce genetic dama ge leading to cell death. However, increasing evidence firmly suggests that the underlying mechanism for anthracycline cytotoxicity is the induction o f apoptosis through intracellular-mediated signaling path ways. Whether dru g/DNA interaction is necessary for such apoptosis signaling is unknown. We investigated the cellular effects of the anthracyclines daunorubicin (DNR) and doxorubicin (DOX) using the myeloid leukemia cell line U937. By compari ng free drug against agarose bead-immobilized drug iDNR and iDOX (which can not accumulate within the cell), me observed that whereas both free and imm obilized anthracyclines were cytotoxic, only the former induced apoptosis; the latter induced necrosis. Indeed, we did not observe ceramide generation , neutral sphingomyelinase activation, poly (ADP-ribose) polymerase cleavag e, or other apoptotic events with iDNR or iDOX. However, both free and immo bilized drug were similarly capable of triggering nuclear factor kappaB act ivation. These observations demonstrate that whereas activation of certain cellular signaling pathways can be achieved solely through membrane interac tion, apoptosis signaling requires anthracycline internalization. These res ults also show that the initiation of cell survival pathways (illustrated b y nuclear factor kappaB activation) is independent of intracellular drug/ta rget interaction.